Methods and compositions for the specific inhibition of HIF-1α by double-stranded RNA

ABSTRACT

This invention relates to compounds, compositions, and methods useful for reducing HIF-1α target RNA and protein levels via use of dsRNAs, e.g., Dicer substrate siRNA (DsiRNA) agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/942,014, filed Jul. 15, 2013 which is a continuation ofPCT/US2012/022045, filed Jan. 20, 2012, which claims priority to, andthe benefit under 35 U.S.C. § 119(e) of, U.S. provisional patentapplication No. 61/435,304, filed Jan. 22, 2011, entitled “Methods andCompositions for the Specific Inhibition of HIF-1α by Double-StrandedRNA”. The entire teachings of this application are incorporated hereinby reference.

FIELD OF THE INVENTION

The present invention relates to compounds, compositions, and methodsfor the study, diagnosis, and treatment of traits, diseases andconditions that respond to the modulation of HIF-1α gene expressionand/or activity.

BACKGROUND OF THE INVENTION

Most locally advanced solid tumors contain regions of reduced oxygenavailability (Vaupel and Mayer, Cancer Metastasis Rev. 26: 225-339;Semenza G L, Drug Discovery Today 12: 853-859). Intratumoral hypoxiaresults when cells are located too far from a functional blood vesselfor diffusion of adequate amounts of oxygen (O₂), as a result of rapidcancer cell proliferation and the formation of blood vessels that arestructurally and functionally abnormal. In the most extreme case, O₂concentrations are below those required for survival, resulting in celldeath and establishing a selection for cancer cells in which apoptoticpathways are inactivated, anti-apoptotic pathways are activated, orinvasion/metastasis pathways that promote escape from the hypoxicmicroenvironment are activated. This hypoxic adaptation may arise byalterations in gene expression or by mutations in the genome or both andis associated with decreased patient survival (Ibid.).

In addition to this intratumoral role for hypoxia, systemic, local, andintracellular homeostatic responses elicited by hypoxia includeerythropoiesis by individuals who are anemic or at high altitude(Jelkmann (1992) Physiol. Rev. 72:449-489), neovascularization inischemic myocardium (White et al. (1992) Circ. Res. 71:1490-1500), andglycolysis in cells cultured at reduced oxygen tension (Wolfle et al.(1983) Eur. J. Biochem. 135:405-412). These adaptive responses eitherincrease oxygen delivery or activate alternate metabolic pathways thatdo not require oxygen. Hypoxia-inducible gene products that participatein these responses include erythropoietin (EPO) (reviewed in Semenza(1994) Hematol. Oncol. Clinics N. Amer. 8:863-884), vascular endothelialgrowth factor (Shweiki et al. (1992) Nature 359:843-845; Banai et al.(1994) Cardiovasc. Res. 28:1176-1179; Goldberg & Schneider (1994) J.Biol. Chern. 269:4355-4359), and glycolytic enzymes (Firth et al. (1994)Proc. Natl. Acad. Sci. USA 91:6496-6500; Semenza et al. (1994) J. Biol.Chern. 269: 23757-23763; Semenza U.S. Pat. No. 5,882,914).

Investigation of the molecular regulation of hypoxia and the EPO gene,which encodes a growth factor that regulates erythropoiesis and thusblood oxygen carrying capacity (Jelkmann (1992) supra; Semenza (1994)supra), resulted in identification of cis-acting DNA sequences in theEPO 3′-flanking region required for transcriptional activation inresponse to hypoxia. HIF-1 (hypoxia inducible factor 1) was identifiedas a trans-acting factor that binds to this enhancer. Previously knowninducers of EPO expression (1% oxygen, cobalt chloride (CoCl₂) anddesferrioxamine (DFX or, alternatively, DFO herein)) also induced HIF-1DNA binding activity with similar kinetics; inhibitors of EPO expression(actinomycin D, cycloheximide, and 2-aminopurine) blocked induction ofHIF-1 activity; and mutations in the EPO 3′-flanking region thateliminated HIF-1 binding also eliminated enhancer function (Semenza(1994) supra).

HIF-1 is a dimer composed of HIF-1α and HIF-1β subunits. HIF-1α is abasic helix-loop-helix (bHLH) transcription factor encoded by the HIF1Agene (Semenza et al., Genomics 34: 437-9; Hogenesch et al., J. Biol.Chem. 272: 8581-93). While the HIF-1β subunit is constitutivelyexpressed, the HIF-1α subunit is the limiting member of the heterodimerand therefore regulates HIF-1 levels. Under conditions of normal oxygen,HIF-1α is ubiquinated and rapidly degraded. However, under hypoxicconditions the rate of ubiquitination dramatically decreases and HIF-1αis stabilized, resulting in upregulation of HIF-1 dimer. This is animportant point and provides a rationale for targeting HIF-1α instead ofHIF-1β for modulating HIF-1 activity (Akinc et al., U.S. Pat. No.7,737,265).

Notably, HIF-1α overexpression has been associated with increasedpatient mortality in a variety of cancers (Semenza G L, Drug DiscoveryToday 12: 853-859), and a role for HIF-1α has also been described, e.g.,for both “wet” and “dry” forms of age-related macular degeneration (AMD;see Akinc et al., supra).

Double-stranded RNA (dsRNA) agents possessing strand lengths of 25 to 35nucleotides have been described as effective inhibitors of target geneexpression in mammalian cells (Rossi et al., U.S. Patent ApplicationNos. 2005/0244858 and US 2005/0277610). dsRNA agents of such length arebelieved to be processed by the Dicer enzyme of the RNA interference(RNAi) pathway, leading such agents to be termed “Dicer substrate siRNA”(“DsiRNA”) agents. Additional modified structures of DsiRNA agents werepreviously described (Rossi et al., U.S. Patent Application No.2007/0265220).

BRIEF SUMMARY OF THE INVENTION

The present invention is directed to compositions that contain doublestranded RNA (“dsRNA”), and methods for preparing them. The dsRNAs ofthe invention are capable of reducing the expression of a target HIF-1αgene in a cell, either in vitro or in a mammalian subject.

In one aspect, the invention provides an isolated double strandednucleic acid (dsNA) having first and second nucleic acid strandsincluding RNA, where the first strand is 15-35 nucleotides in length andthe second strand of the dsNA is 19-35 nucleotides in length, and wherethe second oligonucleotide strand is sufficiently complementary to atarget HIF-1α mRNA sequence of Table 12 along at least 15 nucleotides ofthe second oligonucleotide strand length to reduce HIF-1α target mRNAexpression when the double stranded nucleic acid is introduced into amammalian cell.

In another aspect, the invention provides an isolated dsNA having firstand second nucleic acid strands, where the first strand is 15-35nucleotides in length and the second strand of the dsNA is 19-35nucleotides in length, where the second oligonucleotide strand issufficiently complementary to a target HIF-1α mRNA sequence of Table 11along at least 19 nucleotides of the second oligonucleotide strandlength to reduce HIF-1α target mRNA expression when the double strandednucleic acid is introduced into a mammalian cell.

In an additional aspect, the invention provides an isolated dsNA havingfirst and second nucleic acid strands, where the first strand is 15-35nucleotides in length and the second strand of the dsNA is 19-35nucleotides in length, where the second oligonucleotide strand issufficiently complementary to a target HIF-1α mRNA sequence of Table 10along at least 19 nucleotides of the second oligonucleotide strandlength to reduce HIF-1α target mRNA expression, and where, starting fromthe 5′ end of the HIF-1α mRNA sequence of Table 10 (position 1),mammalian Ago2 cleaves the mRNA at a site between positions 9 and 10 ofthe sequence, when the double stranded nucleic acid is introduced into amammalian cell.

In a further aspect, the invention provides an isolated dsNA consistingof (1) a sense region and an antisense region, where the sense regionand the antisense region together form a duplex region of 25-35 basepairs and the antisense region has a sequence that is the complement ofa sequence of Table 10; and (2) from zero to two 3′ overhang regions,where each overhang region is six or fewer nucleotides in length.

In another aspect, the invention provides an isolated dsNA having firstand second nucleic acid strands and a duplex region of at least 25 basepairs, where the first strand is 25-34 nucleotides in length and thesecond strand of the dsNA is 26-35 nucleotides in length and has 1-5single-stranded nucleotides at its 3′ terminus, where the secondoligonucleotide strand is sufficiently complementary to a target HIF-1αmRNA sequence of Table 5 along at least 19 nucleotides of the secondoligonucleotide strand length to reduce HIF-1α target gene expressionwhen the double stranded nucleic acid is introduced into a mammaliancell.

In an additional aspect, the invention provides an isolated dsNA havingfirst and second nucleic acid strands and a duplex region of at least 25base pairs, where the first strand is 25-34 nucleotides in length andthe second strand of the dsNA is 26-35 nucleotides in length andincludes 1-5 single-stranded nucleotides at its 3′ terminus, where the3′ terminus of the first oligonucleotide strand and the 5′ terminus ofthe second oligonucleotide strand form a blunt end, and the secondoligonucleotide strand is sufficiently complementary to a target HIF-1αsequence of SEQ ID NOs: 757-1134, 1630-2007 or 3144-4191 along at least19 nucleotides of the second oligonucleotide strand length to reduceHIF-1α mRNA expression when the double stranded nucleic acid isintroduced into a mammalian cell.

In one embodiment, the isolated dsNA has a duplex region of at least 25base pairs.

In another embodiment, the isolated dsNA has a duplex region of 19-21base pairs.

In another embodiment, the isolated dsNA has a duplex region of 21-25base pairs.

In another embodiment, the second oligonucleotide strand presents 1-5single-stranded nucleotides at its 3′ terminus.

In one embodiment, the first strand is 25-35 nucleotides in length.Optionally, the second strand is 25-35 nucleotides in length.

The invention also provides for an isolated dsNA wherein the firststrand is 26-35 nucleotides in length, 27-35 nucleotides in length,28-35 nucleotides in length, 29-35 nucleotides in length, 30-35nucleotides in length, 31-35 nucleotides in length, 33-35 nucleotides inlength, 34-35 nucleotides in length, 17-35 nucleotides in length, 19-35nucleotides in length, 21-35 nucleotides in length, 23-35 nucleotides inlength, 17-33 nucleotides in length, 17-31 nucleotides in length, 17-29nucleotides in length, 17-27 nucleotides in length, 21-35 nucleotides inlength or 19-33 nucleotides in length.

The invention also provides for an isolated dsNA wherein the secondstrand is 26-35 nucleotides in length, 27-35 nucleotides in length,28-35 nucleotides in length, 29-35 nucleotides in length, 30-35nucleotides in length, 31-35 nucleotides in length, 33-35 nucleotides inlength, 34-35 nucleotides in length, 21-35 nucleotides in length, 23-35nucleotides in length, 25-35 nucleotides in length, 27-35 nucleotides inlength, 19-33 nucleotides in length, 19-31 nucleotides in length, 19-29nucleotides in length, 19-27 nucleotides in length or 19-25 nucleotidesin length.

In another embodiment, the second oligonucleotide strand iscomplementary to a target HIF-1α cDNA sequence of GenBank Accession Nos.NM_001530.3 or NM_181054.2 along at most 27 nucleotides of the secondoligonucleotide strand length.

In a further embodiment, starting from the first nucleotide (position 1)at the 3′ terminus of the first oligonucleotide strand of the dsNA,position 1, 2 and/or 3 is substituted with a modified nucleotide.

In another embodiment, the 3′ terminus of the first strand and the 5′terminus of the second strand form a blunt end.

Optionally, the first strand is 25 nucleotides in length and the secondstrand is 27 nucleotides in length.

In another embodiment, starting from the 5′ end of a HIF-1α mRNAsequence of Table 10 (position 1), mammalian Ago2 cleaves the HIF-1αmRNA at a site between positions 9 and 10 of the sequence, therebyreducing HIF-1α target mRNA expression when the double stranded nucleicacid is introduced into a mammalian cell.

In a related embodiment, starting from the 5′ end of a HIF-1α mRNAsequence of SEQ ID NOs: 757-1134, mammalian Ago2 cleaves the mRNA at asite between positions 9 and 10 of the cDNA sequence, thereby reducingHIF-1α target mRNA expression when the double stranded nucleic acid isintroduced into a mammalian cell.

In another embodiment, the second strand includes a sequence of SEQ IDNOs: 379-756. Optionally, the first strand includes a sequence of SEQ IDNOs: 1-378.

In a further embodiment, the isolated dsNA includes a pair of firststrand/second strand sequences shown in Table 2.

In one embodiment, each of the first and the second strands is at least26 nucleotides long.

The invention also provides for an isolated dsNA, wherein each of saidfirst and said second strands has a length which is at least 27nucleotides, at least 28 nucleotides, at least 29 nucleotides, at least30 nucleotides, at least 31 nucleotides, at least 32 nucleotides, atleast 33 nucleotides, at least 34 nucleotides or at least 35nucleotides.

In one embodiment, the dsNA includes a modified nucleotide. Optionally,the modified nucleotide residue is 2′-O-methyl, 2′-methoxyethoxy,2′-fluoro, 2′-allyl, 2′-O-[2-(methylamino)-2-oxoethyl], 4′-thio,4′-CH2-O-2′-bridge, 4′-(CH2)2-O-2′-bridge, 2′-LNA, 2′-amino or2′-O—(N-methlycarbamate)

In another embodiment, the modified nucleotide residue of the 3′terminus of the first strand is a deoxyribonucleotide, anacyclonucleotide or a fluorescent molecule. Optionally, position 1 ofthe 3′ terminus of the first oligonucleotide strand is adeoxyribonucleotide.

In another embodiment, the nucleotides of the 1-5 single-strandednucleotides of the 3′ terminus of the second strand include a modifiednucleotide. Optionally, the modified nucleotide is a 2′-O-methylribonucleotide.

In one embodiment, all nucleotides of the 1-5 single-strandednucleotides of the 3′ terminus of the second strand are modifiednucleotides.

In another embodiment, the 1-5 single-stranded nucleotides of the 3′terminus of the second strand are 1-3 nucleotides in length, optionally,1-2 nucleotides in length.

In one embodiment, the 1-5 single-stranded nucleotides of the 3′terminus of the second strand is two nucleotides in length and includesa 2′-O-methyl modified ribonucleotide.

Optionally, the second oligonucleotide strand includes a modificationpattern of AS-M1 to AS-M40 or AS-M1* to AS-M40*. In a relatedembodiment, the first oligonucleotide strand includes a modificationpattern of SM1 to SM16.

In one embodiment, each of the first and the second strands has a lengthwhich is at least 26 and at most 30 nucleotides.

The invention also provides for an isolated dsNA, wherein each of thefirst and the second strands has a length which is at least 27 and atmost 30 nucleotides, at least 28 and at most 30 nucleotides and at least29 and at most 30 nucleotides.

In another embodiment, the dsNA is cleaved endogenously in a cell byDicer.

In a further embodiment, the amount of the isolated double strandednucleic acid sufficient to reduce expression of the target gene is 1nanomolar or less, 200 picomolar or less, 100 picomolar or less, 50picomolar or less, 20 picomolar or less, 10 picomolar or less, 5picomolar or less, 2, picomolar or less or 1 picomolar or less in theenvironment of the cell.

In another embodiment, the isolated dsNA possesses greater potency thanan isolated 21mer siRNA directed to the identical at least 19nucleotides of the target HIF-1α mRNA in reducing target HIF-1α mRNAexpression when assayed in vitro in a mammalian cell at an effectiveconcentration in the environment of the cell of 1 nanomolar or less.

In a further embodiment, the isolated dsNA is sufficiently complementaryto the target HIF-1α mRNA sequence to reduce HIF-1α target mRNAexpression by an amount (expressed by %) of at least 10%, at least 50%,at least 80-90%, at least 95%, at least 98%, or at least 99% when thedouble stranded nucleic acid is introduced into a mammalian cell.

The invention provides for an isolated dsNA that is sufficientlycomplementary to a target HIF-1α mRNA sequence along at least 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25 or more nucleotides of the secondoligonucleotide strand length to reduce HIF-1α target mRNA expressionwhen the dsNA is introduced into a mammalian cell.

In one embodiment, the first and second strands are joined by a chemicallinker.

In another embodiment, the 3′ terminus of the first strand and the 5′terminus of the second strand are joined by a chemical linker.

Optionally, a nucleotide of the second or first strand is substitutedwith a modified nucleotide that directs the orientation of Dicercleavage.

In one embodiment, the dsNA has a modified nucleotide that is adeoxyribonucleotide, a dideoxyribonucleotide, an acyclonucleotide, a3′-deoxyadenosine (cordycepin), a 3′-azido-3′-deoxythymidine (AZT), a2′,3′-dideoxyinosine (ddI), a 2′,3′-dideoxy-3′-thiacytidine (3TC), a2′,3′-didehydro-2′,3′-dideoxythymidine (d4T), a monophosphate nucleotideof 3′-azido-3′-deoxythymidine (AZT), a 2′,3′-dideoxy-3′-thiacytidine(3TC) and a monophosphate nucleotide of2′,3′-didehydro-2′,3′-dideoxythymidine (d4T), a 4-thiouracil, a5-bromouracil, a 5-iodouracil, a 5-(3-aminoallyl)-uracil, a 2′-O-alkylribonucleotide, a 2′-O-methyl ribonucleotide, a 2′-amino ribonucleotide,a 2′-fluoro ribonucleotide, or a locked nucleic acid.

In another embodiment, the dsNA has a phosphate backbone modificationthat is a phosphonate, a phosphorothioate or a phosphotriester.

In a further embodiment, the isolated double stranded nucleic acidincludes a morpholino nucleic acid or a peptide nucleic acid (PNA).

Another aspect of the invention provides a method for reducingexpression of a target HIF-1α gene in a mammalian cell that involvescontacting a mammalian cell in vitro with an isolated dsNA of theinvention in an amount sufficient to reduce expression of a targetHIF-1αmRNA in the cell.

In one embodiment, target HIF-1α mRNA expression is reduced by at least10%, at least 50% or at least 80-90%. Optionally, HIF-1α mRNA levels arereduced by at least 90% at least 8 days after the cell is contacted withthe dsNA. In certain embodiments, HIF-1α mRNA levels are reduced by atleast 70% at least 10 days after the cell is contacted with the dsNA.

In another aspect, the invention provides a method for reducingexpression of a target HIF-1α mRNA in a mammal that includesadministering an isolated dsNA of the invention to a mammal in an amountsufficient to reduce expression of a target HIF-1α mRNA in the mammal.

In one embodiment, the isolated dsNA is administered at 1 microgram to 5milligrams per kilogram of the mammal per day, 100 micrograms to 0.5milligrams per kilogram, 0.001 to 0.25 milligrams per kilogram, 0.01 to20 micrograms per kilogram, 0.01 to 10 micrograms per kilogram, 0.10 to5 micrograms per kilogram, or 0.1 to 2.5 micrograms per kilogram.

In another embodiment, the isolated dsNA possesses greater potency thanisolated 21mer siRNAs directed to the identical at least 19 nucleotidesof the target HIF-1α mRNA in reducing target HIF-1α mRNA expression whenassayed in vitro in a mammalian cell at an effective concentration inthe environment of a cell of 1 nanomolar or less.

In one embodiment, HIF-1α mRNA levels are reduced in a tissue of themammal by an amount (expressed by %) of at least 70% at least 4 daysafter the isolated dsNA is administered to the mammal. In a relatedembodiment, the tissue is liver tissue.

Optionally, the administering step involves intravenous injection,intramuscular injection, intraperitoneal injection, infusion,subcutaneous injection, transdermal, aerosol, rectal, vaginal, topical,oral or inhaled delivery.

Another aspect of the invention provides a method for selectivelyinhibiting the growth of a cell involving contacting a cell with anamount of an isolated dsNA of the invention sufficient to inhibit thegrowth of the cell.

In one embodiment, the cell is a tumor cell of a subject. In anotherembodiment, the cell is a tumor cell in vitro.

Optionally, the cell is a human cell.

A further aspect of the invention provides a formulation that includesthe isolated dsNA of the invention present in an amount effective toreduce target HIF-1α mRNA levels when the dsNA is introduced into amammalian cell in vitro by at least 10%, at least 50% or at least80-90%.

In one embodiment, the effective amount is 1 nanomolar or less, 200picomolar or less, 100 picomolar or less, 50 picomolar or less, 20picomolar or less, 10 picomolar or less, 5 picomolar or less, 2,picomolar or less or 1 picomolar or less in the environment of the cell.

Another aspect of the invention provides a formulation having anisolated dsNA of the invention, where the dsNA is present in an amounteffective to reduce target HIF-1α mRNA levels when the dsNA isintroduced into a cell of a mammalian subject by an amount (expressed by%) of at least 10%, at least 50% or at least 80-90%.

In one embodiment, the effective amount is a dosage of 1 microgram to 5milligrams per kilogram of the subject per day, 100 micrograms to 0.5milligrams per kilogram, 0.001 to 0.25 milligrams per kilogram, 0.01 to20 micrograms per kilogram, 0.01 to 10 micrograms per kilogram, 0.10 to5 micrograms per kilogram, or 0.1 to 2.5 micrograms per kilogram.

In another embodiment, the dsNA possesses greater potency than anisolated 21mer siRNA directed to the identical at least 19 nucleotidesof the target HIF-1αmRNA in reducing target HIF-1α mRNA levels whenassayed in vitro in a mammalian cell at an effective concentration inthe environment of a cell of 1 nanomolar or less.

A further aspect of the invention provides a mammalian cell containingan isolated dsNA of the invention.

An additional aspect of the invention provides a pharmaceuticalcomposition having an isolated dsNA of the invention and apharmaceutically acceptable carrier.

Another aspect of the invention provides a kit that includes an isolateddsNA of the invention and instructions for its use.

In an additional aspect, the invention provides a method for treating orpreventing a HIF-1α-associated disease or disorder in a subjectinvolving administering an isolated dsNA of the invention and apharmaceutically acceptable carrier to the subject in an amountsufficient to treat or prevent the HIF-1α-associated disease or disorderin the subject, thereby treating or preventing the HIF-1α-associateddisease or disorder in the subject.

Optionally, the HIF-1α-associated disease or disorder is renal, breast,lung, ovarian, cervical, esophageal, oropharyngeal or pancreatic cancer.

A further aspect of the invention provides a composition possessingHIF-1α inhibitory activity that consists essentially of an isolated dsNAof the invention.

In one aspect, the invention provides an isolated double strandedribonucleic acid (dsRNA) comprising first and second nucleic acidstrands, wherein the first strand is 25-35 nucleotides in length and thesecond strand is 26-35 nucleotides in length, wherein the secondoligonucleotide strand is sufficiently complementary to a target HIF-1αcDNA sequence of SEQ ID NOs: 757-1134, 1630-2007 and/or 3144-4191 alongat least 19 nucleotides of the second oligonucleotide strand length toreduce HIF-1α target gene expression when the double stranded nucleicacid is introduced into a mammalian cell.

The present invention is also directed to compounds, compositions, andmethods relating to traits, diseases and conditions that respond to themodulation of expression and/or activity of genes involved in HIF-1αgene expression pathways or other cellular processes that mediate themaintenance or development of such traits, diseases and conditions. Incertain aspects, the invention relates to small nucleic acid moleculesthat are capable of being processed by the Dicer enzyme, such as Dicersubstrate siRNAs (DsiRNAs) capable of mediating RNA interference (RNAi)against HIF-1α gene expression. The anti-HIF-1α dsRNAs of the inventionare useful, for example, in providing compositions for treatment oftraits, diseases and conditions that can respond to modulation of HIF-1αin a subject, such as cancer and/or other proliferative diseases,disorders, or conditions. Efficacy, potency, toxicity and other effectsof an anti-HIF-1α dsRNA can be examined in one or more animal models ofproliferative disease (exemplary animal models of proliferative diseaseare recited below).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the structures of exemplary DsiRNA agents of the inventiontargeting a site in the HIF-1α RNA referred to herein as the“HIF-1α-1385” target site. UPPER case=unmodified RNA, lower case=DNA,Bold=mismatch base pair nucleotides; arrowheads indicate projected Dicerenzyme cleavage sites; dashed line indicates sense strand (top strand)sequences corresponding to the projected Argonaute 2 (Ago2) cleavagesite within the targeted HIF-1α sequence.

FIGS. 2A to 2D present primary screen data showing DsiRNA-mediatedknockdown of human HIF-1α (FIGS. 2A and 2B) and mouse HIF-1α (FIGS. 2Cand 2D) in human and mouse cells, respectively. For each DsiRNA tested,two independent qPCR amplicons were assayed (in human cells, amplicons“815-1008” and “2690-2866” were assayed, while in mouse cells, amplicons“1055-1223” and “2463-2593” were assayed). The boxed region of FIG. 2Dindicates a series of assays known to have been affected by sub-optimaltransfection conditions.

FIGS. 3A to 3F show histograms of human and mouse HIF-1α inhibitoryefficacies observed for indicated DsiRNAs. “P1” indicates phase 1(primary screen), while “P2” indicates phase 2. In phase 1, DsiRNAs weretested at 1 nM in the environment of HeLa cells (human cell assays;FIGS. 3A to 3C) or mouse cells (Hepa1-6 cell assays; FIGS. 3D to 3F). Inphase 2, DsiRNAs were tested at 1 nM, at 0.3 nM and at 0.1 nM in theenvironment of HeLa cells. Individual bars represent average human (FIG.3A to 3C) or mouse (FIGS. 3D to 3F) HIF-1α levels observed intriplicate, with standard errors shown. Human HIF-1α levels werenormalized to HPRT and SFRS9 levels, while mouse HIF-1α levels werenormalized to HPRT and Rp123 levels.

FIGS. 4A to 4X present bar graphs showing efficacy data for fourdifferent 2′-O-methyl modification patterns (“M8”, “M4”, “M3” and “M1”,respectively) each across 24 HIF-1α-targeting DsiRNAs in human HeLacells at 0.1 nM, 0.3 nM and 1 nM.

FIG. 5 shows that delivery of a HIF-1α-targeting DsiRNA (HIF-1α-1385,possessing 2′-O-methyl modification pattern “M4”) to human HeLa cellseffectively and dramatically reduced HIF-1α protein levels. DsiRNAtransfection of HeLa cells occurred on day 0, with desferrioxamine (DFO)added to indicated HeLa cells on day 1 to induce HIF-1α expression. Onday 2, HeLa cells were harvested and nuclear proteins were isolated forWestern blot analysis. The Western blot of FIG. 5 was probed withanti-HIF-1α antibody (top panel), with Lamin A/C protein levels (bottompanel, resulting from probing the Western blot with anti-Lamin A/Cantibody) shown for purpose of comparison to HIF-1α protein levels.“Control DsiRNA 114” indicates a non-specific, scrambled control DsiRNA.

FIG. 6 shows HIF-1α inhibitory dose-response curves obtained for sevendistinct HIF-1α-targeting DsiRNAs (two different modified forms ofHIF-1α-1385 DsiRNAs were examined, in addition to single modified formsof each of six other DsiRNAs). IC₅₀ values observed for each DsiRNA werecalculated for each dose-response curve and ranged from 1.41 pM(HIF-1α-4012, possessing 2′-O-methyl modification pattern “M1”) to 42.1pM (HIF-1α-1385, possessing 2′-O-methyl modification pattern “M4”).

FIG. 7 demonstrates that a majority of assayed 25/27mer DsiRNAs weresuperior inhibitors of HIF-1α than corresponding 21mer siRNAs targetingthe same HIF-1α sequence. Data were obtained via pairwise comparison ofa set of forty HIF-1α-targeting 25/27mer DsiRNAs with corresponding21mer siRNAs directed against the same 21 nucleotide HIF-1α target site.All agents (both 25/27mer DsiRNAs and 21mer siRNAs) were assayed at 0.1nM concentration in the environment of HeLa cells in vitro. For 24 ofthe 40 tested anti-HIF-1α 25/27mer DsiRNA agents, statisticallysignificant DsiRNA superiority was observed, as compared to only four offorty siRNA agents that outperformed DsiRNA agents.

FIGS. 8A to 8H show HIF-1α inhibitory activities of HIF-1α-targetingDsiRNAs possessing 2′-O-methyl modification patterns of both guide andpassenger strands, when administered to human HeLa cells (FIG. 8A to 8D)or mouse Hepa 1-6 cells (FIG. 8E to 8H) at 1 nM or 0.1 nMconcentrations.

FIG. 9 shows that eight distinct HIF-1α-targeting DsiRNAs possessingmodified guide strands were robustly effective inhibitors of HIF-1αlevels in vivo, when formulated and delivered to CD1 mice. Levels ofHIF-1α mRNA in normal liver at three days post-administration wereassayed and are shown.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compositions that contain doublestranded RNA (“dsRNA”), and methods for preparing them, that are capableof reducing the level and/or expression of the HIF-1α gene in vivo or invitro. One of the strands of the dsRNA contains a region of nucleotidesequence that has a length that ranges from 19 to 35 nucleotides thatcan direct the destruction and/or translational inhibition of thetargeted HIF-1α transcript.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the meaning commonly understood by a person skilled in the art towhich this invention belongs. The following references provide one ofskill with a general definition of many of the terms used in thisinvention: Singleton et al., Dictionary of Microbiology and MolecularBiology (2nd ed. 1994); The Cambridge Dictionary of Science andTechnology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R.Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, TheHarper Collins Dictionary of Biology (1991). As used herein, thefollowing terms have the meanings ascribed to them below, unlessspecified otherwise.

The present invention features one or more DsiRNA molecules that canmodulate (e.g., inhibit) HIF-1α expression. The DsiRNAs of the inventionoptionally can be used in combination with modulators of other genesand/or gene products associated with the maintenance or development ofdiseases or disorders associated with HIF-1α misregulation (e.g., tumorformation and/or growth, etc.). The DsiRNA agents of the inventionmodulate HIF-1αRNAs such as those corresponding to the cDNA sequencesreferred to by GenBank Accession Nos. NM_001530.3 (human HIF-1α,transcript variant 1), NM_181054.2 (human HIF-1α, transcript variant 2)and NM_010431.2 (mouse HIF-1α), which are recited below and referred toherein generally as “HIF-1α.”

The below description of the various aspects and embodiments of theinvention is provided with reference to exemplary HIF-1α RNAs, generallyreferred to herein as HIF-1α. However, such reference is meant to beexemplary only and the various aspects and embodiments of the inventionare also directed to alternate HIF-1α RNAs, such as mutant HIF-1α RNAsor additional HIF-1α splice variants. Certain aspects and embodimentsare also directed to other genes involved in HIF-1α pathways, includinggenes whose misregulation acts in association with that of HIF-1α (or isaffected or affects HIF-1α regulation) to produce phenotypic effectsthat may be targeted for treatment (e.g., tumor formation and/or growth,etc.). (The EGFR pathway and angiogenesis are examples of pathways forwhich misregulation of genes acts in association with that of HIF-1α.)Such additional genes can be targeted using dsRNA and the methodsdescribed herein for use of HIF-1α targeting dsRNAs. Thus, theinhibition and the effects of such inhibition of the other genes can beperformed as described herein.

The term “HIF-1α” refers to nucleic acid sequences encoding a HIF-1αprotein, peptide, or polypeptide (e.g., HIF-1α transcripts, such as thesequences of HIF-1α Genbank Accession Nos. NM_001530.3, NM_181054.2 andNM_010431.2). In certain embodiments, the term “HIF-1α” is also meant toinclude other HIF-1α encoding sequence, such as other HIF-1α isoforms,mutant HIF-1α genes, splice variants of HIF-1α genes, and HIF-1α genepolymorphisms. The term “HIF-1α” is also used to refer to thepolypeptide gene product of a HIF-1α gene/transcript, e.g., a HIF-1αprotein, peptide, or polypeptide, such as those encoded by HIF-1αGenbank Accession Nos. NM_001530.3, NM_181054.2 and NM_010431.2.

As used herein, a “HIF-1α-associated disease or disorder” refers to adisease or disorder known in the art to be associated with alteredHIF-1α expression, level and/or activity. Notably, a “HIF-1α-associateddisease or disorder” includes cancer and/or proliferative diseases,conditions, or disorders, as well as age-related macular degeneration(AMD). Exemplary “HIF-1α-associated disease or disorders” includebladder, brain, breast, cervical (uterine), colorectal, endometrial(uterine), esophageal, head and neck, liver, lung (NSCLC),oropharyngeal, ovarian, pancreatic, renal, skin (melanoma) and stomach(GIST) cancers.

By “proliferative disease” or “cancer” as used herein is meant, adisease, condition, trait, genotype or phenotype characterized byunregulated cell growth or replication as is known in the art; includingleukemias, for example, acute myelogenous leukemia (AML), chronicmyelogenous leukemia (CML), acute lymphocytic leukemia (ALL), andchronic lymphocytic leukemia, AIDS related cancers such as Kaposi'ssarcoma; breast cancers; bone cancers such as Osteosarcoma,Chondrosarcomas, Ewing's sarcoma, Fibrosarcomas, Giant cell tumors,Adamantinomas, and Chordomas; Brain cancers such as Meningiomas,Glioblastomas, Lower-Grade Astrocytomas, Oligodendrocytomas, PituitaryTumors, Schwannomas, and Metastatic brain cancers; cancers of the headand neck including various lymphomas such as mantle cell lymphoma,non-Hodgkins lymphoma, adenoma, squamous cell carcinoma, laryngealcarcinoma, gallbladder and bile duct cancers, cancers of the retina suchas retinoblastoma, cancers of the esophagus, gastric cancers, multiplemyeloma, ovarian cancer, uterine cancer, thyroid cancer, testicularcancer, endometrial cancer, melanoma, colorectal cancer, lung cancer,bladder cancer, prostate cancer, lung cancer (including non-small celllung carcinoma), pancreatic cancer, sarcomas, Wilms' tumor, cervicalcancer, head and neck cancer, skin cancers, nasopharyngeal carcinoma,liposarcoma, epithelial carcinoma, renal cell carcinoma, gallbladderadeno carcinoma, parotid adenocarcinoma, endometrial sarcoma, multidrugresistant cancers; and proliferative diseases and conditions, such asneovascularization associated with tumor angiogenesis, maculardegeneration (e.g., wet/dry AMD), corneal neovascularization, diabeticretinopathy, neovascular glaucoma, myopic degeneration and otherproliferative diseases and conditions such as restenosis and polycystickidney disease, and other cancer or proliferative disease, condition,trait, genotype or phenotype that can respond to the modulation ofdisease related gene expression in a cell or tissue, alone or incombination with other therapies.

In certain embodiments, dsRNA-mediated inhibition of a HIF-1α targetsequence is assessed. In such embodiments, HIF-1α RNA levels can beassessed by art-recognized methods (e.g., RT-PCR, Northern blot,expression array, etc.), optionally via comparison of HIF-1α levels inthe presence of an anti-HIF-1α dsRNA of the invention relative to theabsence of such an anti-HIF-1αdsRNA. In certain embodiments, HIF-1αlevels in the presence of an anti-HIF-1αdsRNA are compared to thoseobserved in the presence of vehicle alone, in the presence of a dsRNAdirected against an unrelated target RNA, or in the absence of anytreatment.

It is also recognized that levels of HIF-1α protein can be assessed andthat HIF-1α protein levels are, under different conditions, eitherdirectly or indirectly related to HIF-1α RNA levels and/or the extent towhich a dsRNA inhibits HIF-1α expression, thus art-recognized methods ofassessing HIF-1α protein levels (e.g., Western blot,immunoprecipitation, other antibody-based methods, etc.) can also beemployed to examine the inhibitory effect of a dsRNA of the invention.

An anti-HIF-1α dsRNA of the invention is deemed to possess “HIF-1αinhibitory activity” if a statistically significant reduction in HIF-1αRNA (or when the HIF-1α protein is assessed, HIF-1α protein levels) isseen when an anti-HIF-1α dsRNA of the invention is administered to asystem (e.g., cell-free in vitro system), cell, tissue or organism, ascompared to a selected control. The distribution of experimental valuesand the number of replicate assays performed will tend to dictate theparameters of what levels of reduction in HIF-1α RNA (either as a % orin absolute terms) is deemed statistically significant (as assessed bystandard methods of determining statistical significance known in theart). However, in certain embodiments, “HIF-1α inhibitory activity” isdefined based upon a % or absolute level of reduction in the level ofHIF-1α in a system, cell, tissue or organism. For example, in certainembodiments, a dsRNA of the invention is deemed to possess HIF-1αinhibitory activity if at least a 5% reduction or at least a 10%reduction in HIF-1α RNA is observed in the presence of a dsRNA of theinvention relative to HIF-1α levels seen for a suitable control. (Forexample, in vivo HIF-1α levels in a tissue and/or subject can, incertain embodiments, be deemed to be inhibited by a dsRNA agent of theinvention if, e.g., a 5% or 10% reduction in HIF-1α levels is observedrelative to a control.) In certain other embodiments, a dsRNA of theinvention is deemed to possess HIF-1α inhibitory activity if HIF-1α RNAlevels are observed to be reduced by at least 15% relative to a selectedcontrol, by at least 20% relative to a selected control, by at least 25%relative to a selected control, by at least 30% relative to a selectedcontrol, by at least 35% relative to a selected control, by at least 40%relative to a selected control, by at least 45% relative to a selectedcontrol, by at least 50% relative to a selected control, by at least 55%relative to a selected control, by at least 60% relative to a selectedcontrol, by at least 65% relative to a selected control, by at least 70%relative to a selected control, by at least 75% relative to a selectedcontrol, by at least 80% relative to a selected control, by at least 85%relative to a selected control, by at least 90% relative to a selectedcontrol, by at least 95% relative to a selected control, by at least 96%relative to a selected control, by at least 97% relative to a selectedcontrol, by at least 98% relative to a selected control or by at least99% relative to a selected control. In some embodiments, completeinhibition of HIF-1α is required for a dsRNA to be deemed to possessHIF-1α inhibitory activity. In certain models (e.g., cell culture), adsRNA is deemed to possess HIF-1α inhibitory activity if at least a 50%reduction in HIF-1α levels is observed relative to a suitable control.In certain other embodiments, a dsRNA is deemed to possess HIF-1αinhibitory activity if at least an 80% reduction in HIF-1α levels isobserved relative to a suitable control.

By way of specific example, in Example 2 below, a series of DsiRNAstargeting HIF-1α were tested for the ability to reduce HIF-1α mRNAlevels in human HeLa or mouse Hepa 1-6 cells in vitro, at 1 nMconcentrations in the environment of such cells and in the presence of atransfection agent (Lipofectamine™ RNAiMAX, Invitrogen). Within Example2 below, HIF-1α inhibitory activity was ascribed to those DsiRNAs thatwere observed to effect at least a 70% reduction of HIF-1α mRNA levelsunder the assayed conditions. It is contemplated that HIF-1α inhibitoryactivity could also be attributed to a dsRNA under either more or lessstringent conditions than those employed for Example 2 below, even whenthe same or a similar assay and conditions are employed. For example, incertain embodiments, a tested dsRNA of the invention is deemed topossess HIF-1α inhibitory activity if at least a 10% reduction, at leasta 20% reduction, at least a 30% reduction, at least a 40% reduction, atleast a 50% reduction, at least a 60% reduction, at least a 75%reduction, at least an 80% reduction, at least an 85% reduction, atleast a 90% reduction, or at least a 95% reduction in HIF-1α mRNA levelsis observed in a mammalian cell line in vitro at 1 nM dsRNAconcentration or lower in the environment of a cell, relative to asuitable control.

Use of other endpoints for determination of whether a double strandedRNA of the invention possesses HIF-1α inhibitory activity is alsocontemplated. Specifically, in one embodiment, in addition to or as analternative to assessing HIF-1α mRNA levels, the ability of a testeddsRNA to reduce HIF-1α protein levels (e.g., at 48 hours aftercontacting a mammalian cell in vitro or in vivo) is assessed, and atested dsRNA is deemed to possess HIF-1α inhibitory activity if at leasta 10% reduction, at least a 20% reduction, at least a 30% reduction, atleast a 40% reduction, at least a 50% reduction, at least a 60%reduction, at least a 70% reduction, at least a 75% reduction, at leastan 80% reduction, at least an 85% reduction, at least a 90% reduction,or at least a 95% reduction in HIF-1α protein levels is observed in amammalian cell contacted with the assayed double stranded RNA in vitroor in vivo, relative to a suitable control. Additional endpointscontemplated include, e.g., assessment of a phenotype associated withreduction of HIF-1α levels—e.g., reduction of growth of a contactedmammalian cell line in vitro and/or reduction of growth of a tumor invivo, including, e.g., halting or reducing the growth of tumor or cancercell levels as described in greater detail elsewhere herein.

HIF-1α inhibitory activity can also be evaluated over time (duration)and over concentration ranges (potency), with assessment of whatconstitutes a dsRNA possessing HIF-1α inhibitory activity adjusted inaccordance with concentrations administered and duration of timefollowing administration. Thus, in certain embodiments, a dsRNA of theinvention is deemed to possess HIF-1α inhibitory activity if at least a50% reduction in HIF-1α activity is observed/persists at a duration oftime of 2 hours, 5 hours, 10 hours, 1 day, 2 days, 3 days, 4 days, 5days, 6 days, 7 days, 8 days, 9 days, 10 days or more afteradministration of the dsRNA to a cell or organism. In additionalembodiments, a dsRNA of the invention is deemed to be a potent HIF-1αinhibitory agent if HIF-1α inhibitory activity (e.g., in certainembodiments, at least 50% inhibition of HIF-1α) is observed at aconcentration of 1 nM or less, 500 pM or less, 200 pM or less, 100 pM orless, 50 pM or less, 20 pM or less, 10 pM or less, 5 pM or less, 2 pM orless or even 1 pM or less in the environment of a cell, for example,within an in vitro assay for HIF-1α inhibitory activity as describedherein. In certain embodiments, a potent HIF-1α inhibitory dsRNA of theinvention is defined as one that is capable of HIF-1α inhibitoryactivity (e.g., in certain embodiments, at least 20% reduction of HIF-1αlevels) at a formulated concentration of 10 mg/kg or less whenadministered to a subject in an effective delivery vehicle (e.g., aneffective lipid nanoparticle formulation). Preferably, a potent HIF-1αinhibitory dsRNA of the invention is defined as one that is capable ofHIF-1α inhibitory activity (e.g., in certain embodiments, at least 50%reduction of HIF-1α levels) at a formulated concentration of 5 mg/kg orless when administered to a subject in an effective delivery vehicle.More preferably, a potent HIF-1α inhibitory dsRNA of the invention isdefined as one that is capable of HIF-1α inhibitory activity (e.g., incertain embodiments, at least 50% reduction of HIF-1α levels) at aformulated concentration of 5 mg/kg or less when administered to asubject in an effective delivery vehicle. Optionally, a potent HIF-1αinhibitory dsRNA of the invention is defined as one that is capable ofHIF-1α inhibitory activity (e.g., in certain embodiments, at least 50%reduction of HIF-1α levels) at a formulated concentration of 2 mg/kg orless, or even 1 mg/kg or less, when administered to a subject in aneffective delivery vehicle.

In certain embodiments, potency of a dsRNA of the invention isdetermined in reference to the number of copies of a dsRNA present inthe cytoplasm of a target cell that are required to achieve a certainlevel of target gene knockdown. For example, in certain embodiments, apotent dsRNA is one capable of causing 50% or greater knockdown of atarget mRNA when present in the cytoplasm of a target cell at a copynumber of 1000 or fewer RISC-loaded antisense strands per cell. Morepreferably, a potent dsRNA is one capable of producing 50% or greaterknockdown of a target mRNA when present in the cytoplasm of a targetcell at a copy number of 500 or fewer RISC-loaded antisense strands percell. Optionally, a potent dsRNA is one capable of producing 50% orgreater knockdown of a target mRNA when present in the cytoplasm of atarget cell at a copy number of 300 or fewer RISC-loaded antisensestrands per cell.

In further embodiments, the potency of a DsiRNA of the invention can bedefined in reference to a 19 to 23mer dsRNA directed to the same targetsequence within the same target gene. For example, a DsiRNA of theinvention that possesses enhanced potency relative to a corresponding 19to 23mer dsRNA can be a DsiRNA that reduces a target gene by anadditional 5% or more, an additional 10% or more, an additional 20% ormore, an additional 30% or more, an additional 40% or more, or anadditional 50% or more as compared to a corresponding 19 to 23mer dsRNA,when assayed in an in vitro assay as described herein at a sufficientlylow concentration to allow for detection of a potency difference (e.g.,transfection concentrations at or below 1 nM in the environment of acell, at or below 100 pM in the environment of a cell, at or below 10 pMin the environment of a cell, at or below 1 nM in the environment of acell, in an in vitro assay as described herein; notably, it isrecognized that potency differences can be best detected via performanceof such assays across a range of concentrations—e.g., 0.1 pM to 10nM—for purpose of generating a dose-response curve and identifying anIC50 value associated with a DsiRNA/dsRNA).

HIF-1α inhibitory levels and/or HIF-1α levels may also be assessedindirectly, e.g., measurement of a reduction of the size, number and/orrate of growth or spread of polyps or tumors in a subject may be used toassess HIF-1α levels and/or HIF-1α inhibitory efficacy of adouble-stranded nucleic acid of the instant invention.

In certain embodiments, the phrase “consists essentially of” is used inreference to the anti-HIF-1α dsRNAs of the invention. In some suchembodiments, “consists essentially of” refers to a composition thatcomprises a dsRNA of the invention which possesses at least a certainlevel of HIF-1α inhibitory activity (e.g., at least 50% HIF-1αinhibitory activity) and that also comprises one or more additionalcomponents and/or modifications that do not significantly impact theHIF-1α inhibitory activity of the dsRNA. For example, in certainembodiments, a composition “consists essentially of” a dsRNA of theinvention where modifications of the dsRNA of the invention and/ordsRNA-associated components of the composition do not alter the HIF-1αinhibitory activity (optionally including potency or duration of HIF-1αinhibitory activity) by greater than 3%, greater than 5%, greater than10%, greater than 15%, greater than 20%, greater than 25%, greater than30%, greater than 35%, greater than 40%, greater than 45%, or greaterthan 50% relative to the dsRNA of the invention in isolation. In certainembodiments, a composition is deemed to consist essentially of a dsRNAof the invention even if more dramatic reduction of HIF-1α inhibitoryactivity (e.g., 80% reduction, 90% reduction, etc. in efficacy, durationand/or potency) occurs in the presence of additional components ormodifications, yet where HIF-1α inhibitory activity is not significantlyelevated (e.g., observed levels of HIF-1α inhibitory activity are within10% those observed for the isolated dsRNA of the invention) in thepresence of additional components and/or modifications.

As used herein, the term “nucleic acid” refers to deoxyribonucleotides,ribonucleotides, or modified nucleotides, and polymers thereof insingle- or double-stranded form. The term encompasses nucleic acidscontaining known nucleotide analogs or modified backbone residues orlinkages, which are synthetic, naturally occurring, and non-naturallyoccurring, which have similar binding properties as the referencenucleic acid, and which are metabolized in a manner similar to thereference nucleotides. Examples of such analogs include, withoutlimitation, phosphorothioates, phosphoramidates, methyl phosphonates,chiral-methyl phosphonates, 2-O-methyl ribonucleotides, peptide-nucleicacids (PNAs) and unlocked nucleic acids (UNAs; see, e.g., Jensen et al.Nucleic Acids Symposium Series 52: 133-4), and derivatives thereof.

As used herein, “nucleotide” is used as recognized in the art to includethose with natural bases (standard), and modified bases well known inthe art. Such bases are generally located at the 1′ position of anucleotide sugar moiety. Nucleotides generally comprise a base, sugarand a phosphate group. The nucleotides can be unmodified or modified atthe sugar, phosphate and/or base moiety, (also referred tointerchangeably as nucleotide analogs, modified nucleotides, non-naturalnucleotides, non-standard nucleotides and other; see, e.g., Usman andMcSwiggen, supra; Eckstein, et al., International PCT Publication No. WO92/07065; Usman et al, International PCT Publication No. WO 93/15187;Uhlman & Peyman, supra, all are hereby incorporated by referenceherein). There are several examples of modified nucleic acid bases knownin the art as summarized by Limbach, et al, Nucleic Acids Res. 22:2183,1994. Some of the non-limiting examples of base modifications that canbe introduced into nucleic acid molecules include, hypoxanthine, purine,pyridin-4-one, pyridin-2-one, phenyl, pseudouracil, 2,4,6-trimethoxybenzene, 3-methyl uracil, dihydrouridine, naphthyl, aminophenyl,5-alkylcytidines (e.g., 5-methylcytidine), 5-alkyluridines (e.g.,ribothymidine), 5-halouridine (e.g., 5-bromouridine) or 6-azapyrimidinesor 6-alkylpyrimidines (e.g. 6-methyluridine), propyne, and others(Burgin, et al., Biochemistry 35:14090, 1996; Uhlman & Peyman, supra).By “modified bases” in this aspect is meant nucleotide bases other thanadenine, guanine, cytosine and uracil at 1′ position or theirequivalents.

As used herein, “modified nucleotide” refers to a nucleotide that hasone or more modifications to the nucleoside, the nucleobase, pentosering, or phosphate group. For example, modified nucleotides excluderibonucleotides containing adenosine monophosphate, guanosinemonophosphate, uridine monophosphate, and cytidine monophosphate anddeoxyribonucleotides containing deoxyadenosine monophosphate,deoxyguanosine monophosphate, deoxythymidine monophosphate, anddeoxycytidine monophosphate. Modifications include those naturallyoccurring that result from modification by enzymes that modifynucleotides, such as methyltransferases. Modified nucleotides alsoinclude synthetic or non-naturally occurring nucleotides. Synthetic ornon-naturally occurring modifications in nucleotides include those with2′ modifications, e.g., 2′-methoxyethoxy, 2′-fluoro, 2′-allyl,2′-O-[2-(methylamino)-2-oxoethyl], 4′-thio, 4′-CH₂—O-2′-bridge,4′-(CH₂)₂—O-2′-bridge, 2′-LNA or other bicyclic or “bridged” nucleosideanalog, and 2′-O—(N-methylcarbamate) or those comprising base analogs.In connection with 2′-modified nucleotides as described for the presentdisclosure, by “amino” is meant 2′-NH₂ or 2′-O—NH₂, which can bemodified or unmodified. Such modified groups are described, e.g., inEckstein et al., U.S. Pat. No. 5,672,695 and Matulic-Adamic et al., U.S.Pat. No. 6,248,878. “Modified nucleotides” of the instant invention canalso include nucleotide analogs as described above.

In reference to the nucleic acid molecules of the present disclosure,modifications may exist upon these agents in patterns on one or bothstrands of the double stranded ribonucleic acid (dsRNA). As used herein,“alternating positions” refers to a pattern where every other nucleotideis a modified nucleotide or there is an unmodified nucleotide (e.g., anunmodified ribonucleotide) between every modified nucleotide over adefined length of a strand of the dsRNA (e.g., 5′-MNMNMN-3′;3′-MNMNMN-5′; where M is a modified nucleotide and N is an unmodifiednucleotide). The modification pattern starts from the first nucleotideposition at either the 5′ or 3′ terminus according to a positionnumbering convention, e.g., as described herein (in certain embodiments,position 1 is designated in reference to the terminal residue of astrand following a projected Dicer cleavage event of a DsiRNA agent ofthe invention; thus, position 1 does not always constitute a 3′ terminalor 5′ terminal residue of a pre-processed agent of the invention). Thepattern of modified nucleotides at alternating positions may run thefull length of the strand, but in certain embodiments includes at least4, 6, 8, 10, 12, 14 nucleotides containing at least 2, 3, 4, 5, 6 or 7modified nucleotides, respectively. As used herein, “alternating pairsof positions” refers to a pattern where two consecutive modifiednucleotides are separated by two consecutive unmodified nucleotides overa defined length of a strand of the dsRNA (e.g., 5′-MMNNMMNNMMNN-3′;3′-MMNNMMNNMMNN-5′; where M is a modified nucleotide and N is anunmodified nucleotide). The modification pattern starts from the firstnucleotide position at either the 5′ or 3′ terminus according to aposition numbering convention such as those described herein. Thepattern of modified nucleotides at alternating positions may run thefull length of the strand, but preferably includes at least 8, 12, 16,20, 24, 28 nucleotides containing at least 4, 6, 8, 10, 12 or 14modified nucleotides, respectively. It is emphasized that the abovemodification patterns are exemplary and are not intended as limitationson the scope of the invention.

As used herein, “base analog” refers to a heterocyclic moiety which islocated at the 1′ position of a nucleotide sugar moiety in a modifiednucleotide that can be incorporated into a nucleic acid duplex (or theequivalent position in a nucleotide sugar moiety substitution that canbe incorporated into a nucleic acid duplex). In the dsRNAs of theinvention, a base analog is generally either a purine or pyrimidine baseexcluding the common bases guanine (G), cytosine (C), adenine (A),thymine (T), and uracil (U). Base analogs can duplex with other bases orbase analogs in dsRNAs. Base analogs include those useful in thecompounds and methods of the invention, e.g., those disclosed in U.S.Pat. Nos. 5,432,272 and 6,001,983 to Benner and US Patent PublicationNo. 20080213891 to Manoharan, which are herein incorporated byreference. Non-limiting examples of bases include hypoxanthine (I),xanthine (X), 3β-D-ribofuranosyl-(2,6-diaminopyrimidine) (K),3-β-D-ribofuranosyl-(1-methyl-pyrazolo[4,3-d]pyrimidine-5,7(4H,6H)-dione)(P), iso-cytosine (iso-C), iso-guanine (iso-G),1-β-D-ribofuranosyl-(5-nitroindole),1-β-D-ribofuranosyl-(3-nitropyrrole), 5-bromouracil, 2-aminopurine,4-thio-dT, 7-(2-thienyl)-imidazo[4,5-b]pyridine (Ds) andpyrrole-2-carbaldehyde (Pa), 2-amino-6-(2-thienyl)purine (S),2-oxopyridine (Y), difluorotolyl, 4-fluoro-6-methylbenzimidazole,4-methylbenzimidazole, 3-methyl isocarbostyrilyl, 5-methylisocarbostyrilyl, and 3-methyl-7-propynyl isocarbostyrilyl,7-azaindolyl, 6-methyl-7-azaindolyl, imidizopyridinyl,9-methyl-imidizopyridinyl, pyrrolopyrizinyl, isocarbostyrilyl,7-propynyl isocarbostyrilyl, propynyl-7-azaindolyl,2,4,5-trimethylphenyl, 4-methylindolyl, 4,6-dimethylindolyl, phenyl,napthalenyl, anthracenyl, phenanthracenyl, pyrenyl, stilbenzyl,tetracenyl, pentacenyl, and structural derivates thereof (Schweitzer etal., J. Org. Chem., 59:7238-7242 (1994); Berger et al., Nucleic AcidsResearch, 28(15):2911-2914 (2000); Moran et al., J. Am. Chem. Soc.,119:2056-2057 (1997); Morales et al., J. Am. Chem. Soc., 121:2323-2324(1999); Guckian et al., J. Am. Chem. Soc., 118:8182-8183 (1996); Moraleset al., J. Am. Chem. Soc., 122(6):1001-1007 (2000); McMinn et al., J.Am. Chem. Soc., 121:11585-11586 (1999); Guckian et al., J. Org. Chem.,63:9652-9656 (1998); Moran et al., Proc. Natl. Acad. Sci.,94:10506-10511 (1997); Das et al., J. Chem. Soc., Perkin Trans.,1:197-206 (2002); Shibata et al., J. Chem. Soc., Perkin Trans., 1:1605-1611 (2001); Wu et al., J. Am. Chem. Soc., 122(32):7621-7632(2000); O'Neill et al., J. Org. Chem., 67:5869-5875 (2002); Chaudhuri etal., J. Am. Chem. Soc., 117:10434-10442 (1995); and U.S. Pat. No.6,218,108). Base analogs may also be a universal base.

As used herein, “universal base” refers to a heterocyclic moiety locatedat the 1′ position of a nucleotide sugar moiety in a modifiednucleotide, or the equivalent position in a nucleotide sugar moietysubstitution, that, when present in a nucleic acid duplex, can bepositioned opposite more than one type of base without altering thedouble helical structure (e.g., the structure of the phosphatebackbone). Additionally, the universal base does not destroy the abilityof the single stranded nucleic acid in which it resides to duplex to atarget nucleic acid. The ability of a single stranded nucleic acidcontaining a universal base to duplex a target nucleic can be assayed bymethods apparent to one in the art (e.g., UV absorbance, circulardichroism, gel shift, single stranded nuclease sensitivity, etc.).Additionally, conditions under which duplex formation is observed may bevaried to determine duplex stability or formation, e.g., temperature, asmelting temperature (Tm) correlates with the stability of nucleic acidduplexes. Compared to a reference single stranded nucleic acid that isexactly complementary to a target nucleic acid, the single strandednucleic acid containing a universal base forms a duplex with the targetnucleic acid that has a lower Tm than a duplex formed with thecomplementary nucleic acid. However, compared to a reference singlestranded nucleic acid in which the universal base has been replaced witha base to generate a single mismatch, the single stranded nucleic acidcontaining the universal base forms a duplex with the target nucleicacid that has a higher Tm than a duplex formed with the nucleic acidhaving the mismatched base.

Some universal bases are capable of base pairing by forming hydrogenbonds between the universal base and all of the bases guanine (G),cytosine (C), adenine (A), thymine (T), and uracil (U) under base pairforming conditions. A universal base is not a base that forms a basepair with only one single complementary base. In a duplex, a universalbase may form no hydrogen bonds, one hydrogen bond, or more than onehydrogen bond with each of G, C, A, T, and U opposite to it on theopposite strand of a duplex. Preferably, the universal bases does notinteract with the base opposite to it on the opposite strand of aduplex. In a duplex, base pairing between a universal base occurswithout altering the double helical structure of the phosphate backbone.A universal base may also interact with bases in adjacent nucleotides onthe same nucleic acid strand by stacking interactions. Such stackinginteractions stabilize the duplex, especially in situations where theuniversal base does not form any hydrogen bonds with the base positionedopposite to it on the opposite strand of the duplex. Non-limitingexamples of universal-binding nucleotides include inosine,1-β-D-ribofuranosyl-5-nitroindole, and/or1-β-D-ribofuranosyl-3-nitropyrrole (US Pat. Appl. Publ. No. 20070254362to Quay et al.; Van Aerschot et al., An acyclic 5-nitroindazolenucleoside analogue as ambiguous nucleoside. Nucleic Acids Res. 1995Nov. 11; 23(21):4363-70; Loakes et al., 3-Nitropyrrole and 5-nitroindoleas universal bases in primers for DNA sequencing and PCR. Nucleic AcidsRes. 1995 Jul. 11; 23(13):2361-6; Loakes and Brown, 5-Nitroindole as anuniversal base analogue. Nucleic Acids Res. 1994 Oct. 11;22(20):4039-43).

As used herein, “loop” refers to a structure formed by a single strandof a nucleic acid, in which complementary regions that flank aparticular single stranded nucleotide region hybridize in a way that thesingle stranded nucleotide region between the complementary regions isexcluded from duplex formation or Watson-Crick base pairing. A loop is asingle stranded nucleotide region of any length. Examples of loopsinclude the unpaired nucleotides present in such structures as hairpins,stem loops, or extended loops.

As used herein, “extended loop” in the context of a dsRNA refers to asingle stranded loop and in addition 1, 2, 3, 4, 5, 6 or up to 20 basepairs or duplexes flanking the loop. In an extended loop, nucleotidesthat flank the loop on the 5′ side form a duplex with nucleotides thatflank the loop on the 3′ side. An extended loop may form a hairpin orstem loop.

As used herein, “tetraloop” in the context of a dsRNA refers to a loop(a single stranded region) consisting of four nucleotides that forms astable secondary structure that contributes to the stability of anadjacent Watson-Crick hybridized nucleotides. Without being limited totheory, a tetraloop may stabilize an adjacent Watson-Crick base pair bystacking interactions. In addition, interactions among the fournucleotides in a tetraloop include but are not limited tonon-Watson-Crick base pairing, stacking interactions, hydrogen bonding,and contact interactions (Cheong et al., Nature 1990 Aug. 16;346(6285):680-2; Heus and Pardi, Science 1991 Jul. 12; 253(5016):191-4).A tetraloop confers an increase in the melting temperature (Tm) of anadjacent duplex that is higher than expected from a simple model loopsequence consisting of four random bases. For example, a tetraloop canconfer a melting temperature of at least 55° C. in 10 mM NaHPO₄ to ahairpin comprising a duplex of at least 2 base pairs in length. Atetraloop may contain ribonucleotides, deoxyribonucleotides, modifiednucleotides, and combinations thereof. Examples of RNA tetraloopsinclude the UNCG family of tetraloops (e.g., UUCG), the GNRA family oftetraloops (e.g., GAAA), and the CUUG tetraloop. (Woese et al., ProcNatl Acad Sci USA. 1990 November; 87(21):8467-71; Antao et al., NucleicAcids Res. 1991 Nov. 11; 19(21):5901-5). Examples of DNA tetraloopsinclude the d(GNNA) family of tetraloops (e.g., d(GTTA), the d(GNRA))family of tetraloops, the d(GNAB) family of tetraloops, the d(CNNG)family of tetraloops, the d(TNCG) family of tetraloops (e.g., d(TTCG)).(Nakano et al. Biochemistry, 41 (48), 14281-14292, 2002; SHINJI et al.Nippon Kagakkai Koen Yokoshu VOL.78th; NO. 2; PAGE. 731 (2000).)

As used herein, the term “siRNA” refers to a double stranded nucleicacid in which each strand comprises RNA, RNA analog(s) or RNA and DNA.The siRNA comprises between 19 and 23 nucleotides or comprises 21nucleotides. The siRNA typically has 2 bp overhangs on the 3′ ends ofeach strand such that the duplex region in the siRNA comprises 17-21nucleotides, or 19 nucleotides. Typically, the antisense strand of thesiRNA is sufficiently complementary with the target sequence of theHIF-1α gene/RNA.

An anti-HIF-1α DsiRNA of the instant invention possesses strand lengthsof at least 25 nucleotides. Accordingly, in certain embodiments, ananti-HIF-1α DsiRNA contains one oligonucleotide sequence, a firstsequence, that is at least 25 nucleotides in length and no longer than35 or up to 50 or more nucleotides. This sequence of RNA can be between26 and 35, 26 and 34, 26 and 33, 26 and 32, 26 and 31, 26 and 30, and 26and 29 nucleotides in length. This sequence can be 27 or 28 nucleotidesin length or 27 nucleotides in length. The second sequence of the DsiRNAagent can be a sequence that anneals to the first sequence underbiological conditions, such as within the cytoplasm of a eukaryoticcell. Generally, the second oligonucleotide sequence will have at least19 complementary base pairs with the first oligonucleotide sequence,more typically the second oligonucleotide sequence will have 21 or morecomplementary base pairs, or 25 or more complementary base pairs withthe first oligonucleotide sequence. In one embodiment, the secondsequence is the same length as the first sequence, and the DsiRNA agentis blunt ended. In another embodiment, the ends of the DsiRNA agent haveone or more overhangs.

In certain embodiments, the first and second oligonucleotide sequencesof the DsiRNA agent exist on separate oligonucleotide strands that canbe and typically are chemically synthesized. In some embodiments, bothstrands are between 26 and 35 nucleotides in length. In otherembodiments, both strands are between 25 and 30 or 26 and 30 nucleotidesin length. In one embodiment, both strands are 27 nucleotides in length,are completely complementary and have blunt ends. In certain embodimentsof the instant invention, the first and second sequences of ananti-HIF-1α DsiRNA exist on separate RNA oligonucleotides (strands). Inone embodiment, one or both oligonucleotide strands are capable ofserving as a substrate for Dicer. In other embodiments, at least onemodification is present that promotes Dicer to bind to thedouble-stranded RNA structure in an orientation that maximizes thedouble-stranded RNA structure's effectiveness in inhibiting geneexpression. In certain embodiments of the instant invention, theanti-HIF-1α DsiRNA agent is comprised of two oligonucleotide strands ofdiffering lengths, with the anti-HIF-1α DsiRNA possessing a blunt end atthe 3′ terminus of a first strand (sense strand) and a 3′ overhang atthe 3′ terminus of a second strand (antisense strand). The DsiRNA canalso contain one or more deoxyribonucleic acid (DNA) base substitutions.

Suitable DsiRNA compositions that contain two separate oligonucleotidescan be chemically linked outside their annealing region by chemicallinking groups. Many suitable chemical linking groups are known in theart and can be used. Suitable groups will not block Dicer activity onthe DsiRNA and will not interfere with the directed destruction of theRNA transcribed from the target gene. Alternatively, the two separateoligonucleotides can be linked by a third oligonucleotide such that ahairpin structure is produced upon annealing of the two oligonucleotidesmaking up the DsiRNA composition. The hairpin structure will not blockDicer activity on the DsiRNA and will not interfere with the directeddestruction of the target RNA.

As used herein, a dsRNA, e.g., DsiRNA or siRNA, having a sequence“sufficiently complementary” to a target RNA or cDNA sequence (e.g.,HIF-1α mRNA) means that the dsRNA has a sequence sufficient to triggerthe destruction of the target RNA (where a cDNA sequence is recited, theRNA sequence corresponding to the recited cDNA sequence) by the RNAimachinery (e.g., the RISC complex) or process. For example, a dsRNA thatis “sufficiently complementary” to a target RNA or cDNA sequence totrigger the destruction of the target RNA by the RNAi machinery orprocess can be identified as a dsRNA that causes a detectable reductionin the level of the target RNA in an appropriate assay of dsRNA activity(e.g., an in vitro assay as described in Example 2 below), or, infurther examples, a dsRNA that is sufficiently complementary to a targetRNA or cDNA sequence to trigger the destruction of the target RNA by theRNAi machinery or process can be identified as a dsRNA that produces atleast a 5%, at least a 10%, at least a 15%, at least a 20%, at least a25%, at least a 30%, at least a 35%, at least a 40%, at least a 45%, atleast a 50%, at least a 55%, at least a 60%, at least a 65%, at least a70%, at least a 75%, at least a 80%, at least a 85%, at least a 90%, atleast a 95%, at least a 98% or at least a 99% reduction in the level ofthe target RNA in an appropriate assay of dsRNA activity. In additionalexamples, a dsRNA that is sufficiently complementary to a target RNA orcDNA sequence to trigger the destruction of the target RNA by the RNAimachinery or process can be identified based upon assessment of theduration of a certain level of inhibitory activity with respect to thetarget RNA or protein levels in a cell or organism. For example, a dsRNAthat is sufficiently complementary to a target RNA or cDNA sequence totrigger the destruction of the target RNA by the RNAi machinery orprocess can be identified as a dsRNA capable of reducing target mRNAlevels by at least 20% at least 48 hours post-administration of saiddsRNA to a cell or organism. Preferably, a dsRNA that is sufficientlycomplementary to a target RNA or cDNA sequence to trigger thedestruction of the target RNA by the RNAi machinery or process isidentified as a dsRNA capable of reducing target mRNA levels by at least40% at least 72 hours post-administration of said dsRNA to a cell ororganism, by at least 40% at least four, five or seven dayspost-administration of said dsRNA to a cell or organism, by at least 50%at least 48 hours post-administration of said dsRNA to a cell ororganism, by at least 50% at least 72 hours post-administration of saiddsRNA to a cell or organism, by at least 50% at least four, five orseven days post-administration of said dsRNA to a cell or organism, byat least 80% at least 48 hours post-administration of said dsRNA to acell or organism, by at least 80% at least 72 hours post-administrationof said dsRNA to a cell or organism, or by at least 80% at least four,five or seven days post-administration of said dsRNA to a cell ororganism.

The dsRNA molecule can be designed such that every residue of theantisense strand is complementary to a residue in the target molecule.Alternatively, substitutions can be made within the molecule to increasestability and/or enhance processing activity of said molecule.Substitutions can be made within the strand or can be made to residuesat the ends of the strand. In certain embodiments, substitutions and/ormodifications are made at specific residues within a DsiRNA agent. Suchsubstitutions and/or modifications can include, e.g.,deoxy-modifications at one or more residues of positions 1, 2 and 3 whennumbering from the 3′ terminal position of the sense strand of a DsiRNAagent; and introduction of 2′-O-alkyl (e.g., 2′-O-methyl) modificationsat the 3′ terminal residue of the antisense strand of DsiRNA agents,with such modifications also being performed at overhang positions ofthe 3′ portion of the antisense strand and at alternating residues ofthe antisense strand of the DsiRNA that are included within the regionof a DsiRNA agent that is processed to form an active siRNA agent. Thepreceding modifications are offered as exemplary, and are not intendedto be limiting in any manner. Further consideration of the structure ofpreferred DsiRNA agents, including further description of themodifications and substitutions that can be performed upon theanti-HIF-1α DsiRNA agents of the instant invention, can be found below.

Where a first sequence is referred to as “substantially complementary”with respect to a second sequence herein, the two sequences can be fullycomplementary, or they may form one or more, but generally not more than4, 3 or 2 mismatched base pairs upon hybridization, while retaining theability to hybridize under the conditions most relevant to theirultimate application. However, where two oligonucleotides are designedto form, upon hybridization, one or more single stranded overhangs, suchoverhangs shall not be regarded as mismatches with regard to thedetermination of complementarity. For example, a dsRNA comprising oneoligonucleotide 21 nucleotides in length and another oligonucleotide 23nucleotides in length, wherein the longer oligonucleotide comprises asequence of 21 nucleotides that is fully complementary to the shorteroligonucleotide, may yet be referred to as “fully complementary” for thepurposes of the invention.

The term “double-stranded RNA” or “dsRNA”, as used herein, refers to acomplex of ribonucleic acid molecules, having a duplex structurecomprising two anti-parallel and substantially complementary, as definedabove, nucleic acid strands. The two strands forming the duplexstructure may be different portions of one larger RNA molecule, or theymay be separate RNA molecules. Where separate RNA molecules, such dsRNAare often referred to as siRNA (“short interfering RNA”) or DsiRNA(“Dicer substrate siRNAs”). Where the two strands are part of one largermolecule, and therefore are connected by an uninterrupted chain ofnucleotides between the 3′-end of one strand and the 5′ end of therespective other strand forming the duplex structure, the connecting RNAchain is referred to as a “hairpin loop”, “short hairpin RNA” or“shRNA”. Where the two strands are connected covalently by means otherthan an uninterrupted chain of nucleotides between the 3′-end of onestrand and the 5′ end of the respective other strand forming the duplexstructure, the connecting structure is referred to as a “linker”. TheRNA strands may have the same or a different number of nucleotides. Themaximum number of base pairs is the number of nucleotides in theshortest strand of the dsRNA minus any overhangs that are present in theduplex. In addition to the duplex structure, a dsRNA may comprise one ormore nucleotide overhangs. In addition, as used herein, “dsRNA” mayinclude chemical modifications to ribonucleotides, internucleosidelinkages, end-groups, caps, and conjugated moieties, includingsubstantial modifications at multiple nucleotides and including alltypes of modifications disclosed herein or known in the art. Any suchmodifications, as used in an siRNA- or DsiRNA-type molecule, areencompassed by “dsRNA” for the purposes of this specification andclaims.

The phrase “duplex region” refers to the region in two complementary orsubstantially complementary oligonucleotides that form base pairs withone another, either by Watson-Crick base pairing or other manner thatallows for a duplex between oligonucleotide strands that arecomplementary or substantially complementary. For example, anoligonucleotide strand having 21 nucleotide units can base pair withanother oligonucleotide of 21 nucleotide units, yet only 19 bases oneach strand are complementary or substantially complementary, such thatthe “duplex region” consists of 19 base pairs. The remaining base pairsmay, for example, exist as 5′ and 3′ overhangs. Further, within theduplex region, 100% complementarity is not required; substantialcomplementarity is allowable within a duplex region. Substantialcomplementarity refers to complementarity between the strands such thatthey are capable of annealing under biological conditions. Techniques toempirically determine if two strands are capable of annealing underbiological conditions are well know in the art. Alternatively, twostrands can be synthesized and added together under biologicalconditions to determine if they anneal to one another.

Single-stranded nucleic acids that base pair over a number of bases aresaid to “hybridize.” Hybridization is typically determined underphysiological or biologically relevant conditions (e.g., intracellular:pH 7.2, 140 mM potassium ion; extracellular pH 7.4, 145 mM sodium ion).Hybridization conditions generally contain a monovalent cation andbiologically acceptable buffer and may or may not contain a divalentcation, complex anions, e.g. gluconate from potassium gluconate,uncharged species such as sucrose, and inert polymers to reduce theactivity of water in the sample, e.g. PEG. Such conditions includeconditions under which base pairs can form.

Hybridization is measured by the temperature required to dissociatesingle stranded nucleic acids forming a duplex, i.e., (the meltingtemperature; Tm). Hybridization conditions are also conditions underwhich base pairs can form. Various conditions of stringency can be usedto determine hybridization (see, e.g., Wahl, G. M. and S. L. Berger(1987) Methods Enzymol. 152:399; Kimmel, A. R. (1987) Methods Enzymol.152:507). Stringent temperature conditions will ordinarily includetemperatures of at least about 30° C., more preferably of at least about37° C., and most preferably of at least about 42° C. The hybridizationtemperature for hybrids anticipated to be less than 50 base pairs inlength should be 5-10° C. less than the melting temperature (Tm) of thehybrid, where Tm is determined according to the following equations. Forhybrids less than 18 base pairs in length, Tm(° C.)=2(# of A+Tbases)+4(# of G+C bases). For hybrids between 18 and 49 base pairs inlength, Tm(° C.)=81.5+16.6(log 10[Na+])+0.41 (% G+C)−(600/N), where N isthe number of bases in the hybrid, and [Na+] is the concentration ofsodium ions in the hybridization buffer ([Na+] for 1×SSC=0.165 M). Forexample, a hybridization determination buffer is shown in Table 1.

TABLE 1 To make 50 final conc. Vender Cat# Lot# m.w./Stock mL solutionNaCl 100 mM  Sigma S-5150 41K8934 5M 1 mL KCl 80 mM Sigma P-9541 70K0002 74.55 0.298 g MgCl₂  8 mM Sigma M-1028 120K8933  1M 0.4 mL sucrose 2%w/v Fisher BP220-212  907105 342.3 1 g Tris-HCl 16 mM Fisher BP1757-500 12419 1M 0.8 mL NaH₂PO₄  1 mM Sigma S-3193 52H- 120.0 0.006 g 029515EDTA 0.02 mM   Sigma E-7889 110K89271 0.5M   2 μL H₂O Sigma W-450251K2359 to 50 mL pH = 7.0 adjust with HCl at 20° C.

Useful variations on hybridization conditions will be readily apparentto those skilled in the art. Hybridization techniques are well known tothose skilled in the art and are described, for example, in Benton andDavis (Science 196:180, 1977); Grunstein and Hogness (Proc. Natl. Acad.Sci., USA 72:3961, 1975); Ausubel et al. (Current Protocols in MolecularBiology, Wiley Interscience, New York, 2001); Berger and Kimmel(Antisense to Molecular Cloning Techniques, 1987, Academic Press, NewYork); and Sambrook et al., Molecular Cloning: A Laboratory Manual, ColdSpring Harbor Laboratory Press, New York.

As used herein, “oligonucleotide strand” is a single stranded nucleicacid molecule. An oligonucleotide may comprise ribonucleotides,deoxyribonucleotides, modified nucleotides (e.g., nucleotides with 2′modifications, synthetic base analogs, etc.) or combinations thereof.Such modified oligonucleotides can be preferred over native formsbecause of properties such as, for example, enhanced cellular uptake andincreased stability in the presence of nucleases.

As used herein, the term “ribonucleotide” encompasses natural andsynthetic, unmodified and modified ribonucleotides. Modificationsinclude changes to the sugar moiety, to the base moiety and/or to thelinkages between ribonucleotides in the oligonucleotide. As used herein,the term “ribonucleotide” specifically excludes a deoxyribonucleotide,which is a nucleotide possessing a single proton group at the 2′ ribosering position.

As used herein, the term “deoxyribonucleotide” encompasses natural andsynthetic, unmodified and modified deoxyribonucleotides. Modificationsinclude changes to the sugar moiety, to the base moiety and/or to thelinkages between deoxyribonucleotide in the oligonucleotide. As usedherein, the term “deoxyribonucleotide” also includes a modifiedribonucleotide that does not permit Dicer cleavage of a dsRNA agent,e.g., a 2′-O-methyl ribonucleotide, a phosphorothioate-modifiedribonucleotide residue, etc., that does not permit Dicer cleavage tooccur at a bond of such a residue.

As used herein, the term “PS-NA” refers to a phosphorothioate-modifiednucleotide residue. The term “PS-NA” therefore encompasses bothphosphorothioate-modified ribonucleotides (“PS-RNAs”) andphosphorothioate-modified deoxyribonucleotides (“PS-DNAs”).

As used herein, “Dicer” refers to an endoribonuclease in the RNase IIIfamily that cleaves a dsRNA or dsRNA-containing molecule, e.g.,double-stranded RNA (dsRNA) or pre-microRNA (miRNA), intodouble-stranded nucleic acid fragments 19-25 nucleotides long, usuallywith a two-base overhang on the 3′ end. With respect to certain dsRNAsof the invention (e.g., “DsiRNAs”), the duplex formed by a dsRNA regionof an agent of the invention is recognized by Dicer and is a Dicersubstrate on at least one strand of the duplex. Dicer catalyzes thefirst step in the RNA interference pathway, which consequently resultsin the degradation of a target RNA. The protein sequence of human Diceris provided at the NCBI database under accession number NP_085124,hereby incorporated by reference.

Dicer “cleavage” can be determined as follows (e.g., see Collingwood etal., Oligonucleotides 18:187-200 (2008)). In a Dicer cleavage assay, RNAduplexes (100 pmol) are incubated in 20 μL of 20 mM Tris pH 8.0, 200 mMNaCl, 2.5 mM MgCl2 with or without 1 unit of recombinant human Dicer(Stratagene, La Jolla, Calif.) at 37° C. for 18-24 hours. Samples aredesalted using a Performa SR 96-well plate (Edge Biosystems,Gaithersburg, Md.). Electrospray-ionization liquid chromatography massspectroscopy (ESI-LCMS) of duplex RNAs pre- and post-treatment withDicer is done using an Oligo HTCS system (Novatia, Princeton, N.J.; Hailet al., 2004), which consists of a ThermoFinnigan TSQ7000, Xcalibur datasystem, ProMass data processing software and Paradigm MS4 HPLC (MichromBioResources, Auburn, Calif.). In this assay, Dicer cleavage occurswhere at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, oreven 100% of the Dicer substrate dsRNA, (i.e., 25-30 bp, dsRNA,preferably 26-30 bp dsRNA) is cleaved to a shorter dsRNA (e.g., 19-23 bpdsRNA, preferably, 21-23 bp dsRNA).

As used herein, “Dicer cleavage site” refers to the sites at which Dicercleaves a dsRNA (e.g., the dsRNA region of a DsiRNA agent of theinvention). Dicer contains two RNase III domains which typically cleaveboth the sense and antisense strands of a dsRNA. The average distancebetween the RNase III domains and the PAZ domain determines the lengthof the short double-stranded nucleic acid fragments it produces and thisdistance can vary (Macrae et al. (2006) Science 311: 195-8). As shown inFIG. 1, Dicer is projected to cleave certain double-stranded ribonucleicacids of the instant invention that possess an antisense strand having a2 nucleotide 3′ overhang at a site between the 21^(st) and 22^(nd)nucleotides removed from the 3′ terminus of the antisense strand, and ata corresponding site between the 21^(st) and 22^(nd) nucleotides removedfrom the 5′ terminus of the sense strand. The projected and/or prevalentDicer cleavage site(s) for dsRNA molecules distinct from those depictedin FIG. 1 may be similarly identified via art-recognized methods,including those described in Macrae et al. While the Dicer cleavageevents depicted in FIG. 1 generate 21 nucleotide siRNAs, it is notedthat Dicer cleavage of a dsRNA (e.g., DsiRNA) can result in generationof Dicer-processed siRNA lengths of 19 to 23 nucleotides in length.Indeed, in certain embodiments, a double-stranded DNA region may beincluded within a dsRNA for purpose of directing prevalent Dicerexcision of a typically non-preferred 19mer or 20mer siRNA, rather thana 21mer.

As used herein, “overhang” refers to unpaired nucleotides, in thecontext of a duplex having one or more free ends at the 5′ terminus or3′ terminus of a dsRNA. In certain embodiments, the overhang is a 3′ or5′ overhang on the antisense strand or sense strand. In someembodiments, the overhang is a 3′ overhang having a length of betweenone and six nucleotides, optionally one to five, one to four, one tothree, one to two, two to six, two to five, two to four, two to three,three to six, three to five, three to four, four to six, four to five,five to six nucleotides, or one, two, three, four, five or sixnucleotides. “Blunt” or “blunt end” means that there are no unpairednucleotides at that end of the dsRNA, i.e., no nucleotide overhang. Forclarity, chemical caps or non-nucleotide chemical moieties conjugated tothe 3′ end or 5′ end of an siRNA are not considered in determiningwhether an siRNA has an overhang or is blunt ended. In certainembodiments, the invention provides a dsRNA molecule for inhibiting theexpression of the HIF-1α target gene in a cell or mammal, wherein thedsRNA comprises an antisense strand comprising a region ofcomplementarity which is complementary to at least a part of an mRNAformed in the expression of the HIF-1α target gene, and wherein theregion of complementarity is less than 35 nucleotides in length,optionally 19-24 nucleotides in length or 25-30 nucleotides in length,and wherein the dsRNA, upon contact with a cell expressing the HIF-1αtarget gene, inhibits the expression of the HIF-1α target gene by atleast 10%, 25%, or 40%.

A dsRNA of the invention comprises two RNA strands that are sufficientlycomplementary to hybridize to form a duplex structure. One strand of thedsRNA (the antisense strand) comprises a region of complementarity thatis substantially complementary, and generally fully complementary, to atarget sequence, derived from the sequence of an mRNA formed during theexpression of the HIF-1α target gene, the other strand (the sensestrand) comprises a region which is complementary to the antisensestrand, such that the two strands hybridize and form a duplex structurewhen combined under suitable conditions. Generally, the duplex structureis between 15 and 35, optionally between 25 and 30, between 26 and 30,between 18 and 25, between 19 and 24, or between 19 and 21 base pairs inlength. Similarly, the region of complementarity to the target sequenceis between 15 and 35, optionally between 18 and 30, between 25 and 30,between 19 and 24, or between 19 and 21 nucleotides in length. The dsRNAof the invention may further comprise one or more single-strandednucleotide overhang(s). It has been identified that dsRNAs comprisingduplex structures of between 15 and 35 base pairs in length can beeffective in inducing RNA interference, including DsiRNAs (generally ofat least 25 base pairs in length) and siRNAs (in certain embodiments,duplex structures of siRNAs are between 20 and 23, and optionally,specifically 21 base pairs (Elbashir et al., EMBO 20: 6877-6888)). Ithas also been identified that dsRNAs possessing duplexes shorter than 20base pairs can be effective as well (e.g., 15, 16, 17, 18 or 19 basepair duplexes). In certain embodiments, the dsRNAs of the invention cancomprise at least one strand of a length of 19 nucleotides or more. Incertain embodiments, it can be reasonably expected that shorter dsRNAscomprising a sequence complementary to one of the sequences of Table 5,minus only a few nucleotides on one or both ends may be similarlyeffective as compared to the dsRNAs described above and in Tables 2-4and 6-7. Hence, dsRNAs comprising a partial sequence of at least 15, 16,17, 18, 19, 20, or more contiguous nucleotides sufficientlycomplementary to one of the sequences of Table 5, and differing in theirability to inhibit the expression of the HIF-1α target gene in an assayas described herein by not more than 5, 10, 15, 20, 25, or 30%inhibition from a dsRNA comprising the full sequence, are contemplatedby the invention. In one embodiment, at least one end of the dsRNA has asingle-stranded nucleotide overhang of 1 to 5, optionally 1 to 4, incertain embodiments, 1 or 2 nucleotides. Certain dsRNA structures havingat least one nucleotide overhang possess superior inhibitory propertiesas compared to counterparts possessing base-paired blunt ends at bothends of the dsRNA molecule.

As used herein, the term “RNA processing” refers to processingactivities performed by components of the siRNA, miRNA or RNase Hpathways (e.g., Drosha, Dicer, Argonaute2 or other RISCendoribonucleases, and RNaseH), which are described in greater detailbelow (see “RNA Processing” section below). The term is explicitlydistinguished from the post-transcriptional processes of 5′ capping ofRNA and degradation of RNA via non-RISC- or non-RNase H-mediatedprocesses. Such “degradation” of an RNA can take several forms, e.g.deadenylation (removal of a 3′ poly(A) tail), and/or nuclease digestionof part or all of the body of the RNA by one or more of several endo- orexo-nucleases (e.g., RNase III, RNase P, RNase T1, RNase A (1, 2, 3,4/5), oligonucleotidase, etc.).

By “homologous sequence” is meant, a nucleotide sequence that is sharedby one or more polynucleotide sequences, such as genes, gene transcriptsand/or non-coding polynucleotides. For example, a homologous sequencecan be a nucleotide sequence that is shared by two or more genesencoding related but different proteins, such as different members of agene family, different protein epitopes, different protein isoforms orcompletely divergent genes, such as a cytokine and its correspondingreceptors. A homologous sequence can be a nucleotide sequence that isshared by two or more non-coding polynucleotides, such as noncoding DNAor RNA, regulatory sequences, introns, and sites of transcriptionalcontrol or regulation. Homologous sequences can also include conservedsequence regions shared by more than one polynucleotide sequence.Homology does not need to be perfect homology (e.g., 100%), as partiallyhomologous sequences are also contemplated by the instant invention(e.g., 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%,86%, 85%, 84%, 83%, 82%, 81%, 80% etc.). Indeed, design and use of thedsRNA agents of the instant invention contemplates the possibility ofusing such dsRNA agents not only against target RNAs of HIF-1αpossessing perfect complementarity with the presently described dsRNAagents, but also against target HIF-1α RNAs possessing sequences thatare, e.g., only 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%,88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80% etc. complementary to saiddsRNA agents. Similarly, it is contemplated that the presently describeddsRNA agents of the instant invention might be readily altered by theskilled artisan to enhance the extent of complementarity between saiddsRNA agents and a target HIF-1α RNA, e.g., of a specific allelicvariant of HIF-1α (e.g., an allele of enhanced therapeutic interest).Indeed, dsRNA agent sequences with insertions, deletions, and singlepoint mutations relative to the target HIF-1α sequence can also beeffective for inhibition. Alternatively, dsRNA agent sequences withnucleotide analog substitutions or insertions can be effective forinhibition.

Sequence identity may be determined by sequence comparison and alignmentalgorithms known in the art. To determine the percent identity of twonucleic acid sequences (or of two amino acid sequences), the sequencesare aligned for comparison purposes (e.g., gaps can be introduced in thefirst sequence or second sequence for optimal alignment). Thenucleotides (or amino acid residues) at corresponding nucleotide (oramino acid) positions are then compared. When a position in the firstsequence is occupied by the same residue as the corresponding positionin the second sequence, then the molecules are identical at thatposition. The percent identity between the two sequences is a functionof the number of identical positions shared by the sequences (i.e., %homology=# of identical positions/total # of positions×100), optionallypenalizing the score for the number of gaps introduced and/or length ofgaps introduced.

The comparison of sequences and determination of percent identitybetween two sequences can be accomplished using a mathematicalalgorithm. In one embodiment, the alignment generated over a certainportion of the sequence aligned having sufficient identity but not overportions having low degree of identity (i.e., a local alignment). Apreferred, non-limiting example of a local alignment algorithm utilizedfor the comparison of sequences is the algorithm of Karlin and Altschul(1990) Proc. Natl. Acad. Sci. USA 87:2264-68, modified as in Karlin andAltschul (1993) Proc. Natl. Acad. Sci. USA 90:5873-77. Such an algorithmis incorporated into the BLAST programs (version 2.0) of Altschul, etal. (1990) J. Mol. Biol. 215:403-10.

In another embodiment, a gapped alignment the alignment is optimized isformed by introducing appropriate gaps, and percent identity isdetermined over the length of the aligned sequences (i.e., a gappedalignment). To obtain gapped alignments for comparison purposes, GappedBLAST can be utilized as described in Altschul et al., (1997) NucleicAcids Res. 25(17):3389-3402. In another embodiment, a global alignmentthe alignment is optimizedis formed by introducing appropriate gaps, andpercent identity is determined over the entire length of the sequencesaligned. (i.e., a global alignment). A preferred, non-limiting exampleof a mathematical algorithm utilized for the global comparison ofsequences is the algorithm of Myers and Miller, CABIOS (1989). Such analgorithm is incorporated into the ALIGN program (version 2.0) which ispart of the GCG sequence alignment software package. When utilizing theALIGN program for comparing amino acid sequences, a PAM120 weightresidue table, a gap length penalty of 12, and a gap penalty of 4 can beused.

Greater than 80% sequence identity, e.g., 80%, 81%, 82%, 83%, 84%, 85%,86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% oreven 100% sequence identity, between the dsRNA antisense strand and theportion of the HIF-1α RNA sequence is preferred. Alternatively, thedsRNA may be defined functionally as a nucleotide sequence (oroligonucleotide sequence) that is capable of hybridizing with a portionof the HIF-1α RNA (e.g., 400 mM NaCl, 40 mM PIPES pH 6.4, 1 mM EDTA, 50°C. or 70° C. hybridization for 12-16 hours; followed by washing).Additional preferred hybridization conditions include hybridization at70° C. in 1×SSC or 50° C. in 1×SSC, 50% formamide followed by washing at70° C. in 0.3×SSC or hybridization at 70° C. in 4×SSC or 50° C. in4×SSC, 50% formamide followed by washing at 67° C. in 1×SSC. Thehybridization temperature for hybrids anticipated to be less than 50base pairs in length should be 5-10° C. less than the meltingtemperature (Tm) of the hybrid, where Tm is determined according to thefollowing equations. For hybrids less than 18 base pairs in length, Tm(°C.)=2(# of A+T bases)+4(# of G+C bases). For hybrids between 18 and 49base pairs in length, Tm(° C.)=81.5+16.6(log 10[Na+])+0.41 (%G+C)−(600/N), where N is the number of bases in the hybrid, and [Na+] isthe concentration of sodium ions in the hybridization buffer ([Na+] for1×SSC=0.165 M). Additional examples of stringency conditions forpolynucleotide hybridization are provided in Sambrook, J., E. F.Fritsch, and T. Maniatis, 1989, Molecular Cloning: A Laboratory Manual,Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., chapters9 and 11, and Current Protocols in Molecular Biology, 1995, F. M.Ausubel et al., eds., John Wiley & Sons, Inc., sections 2.10 and6.3-6.4. The length of the identical nucleotide sequences may be atleast 10, 12, 15, 17, 20, 22, 25, 27 or 30 bases.

By “conserved sequence region” is meant, a nucleotide sequence of one ormore regions in a polynucleotide does not vary significantly betweengenerations or from one biological system, subject, or organism toanother biological system, subject, or organism. The polynucleotide caninclude both coding and non-coding DNA and RNA.

By “sense region” is meant a nucleotide sequence of a dsRNA moleculehaving complementarity to an antisense region of the dsRNA molecule. Inaddition, the sense region of a dsRNA molecule can comprise a nucleicacid sequence having homology with a target nucleic acid sequence.

By “antisense region” is meant a nucleotide sequence of a dsRNA moleculehaving complementarity to a target nucleic acid sequence. In addition,the antisense region of a dsRNA molecule comprises a nucleic acidsequence having complementarity to a sense region of the dsRNA molecule.

As used herein, “antisense strand” refers to a single stranded nucleicacid molecule which has a sequence complementary to that of a targetRNA. When the antisense strand contains modified nucleotides with baseanalogs, it is not necessarily complementary over its entire length, butmust at least hybridize with a target RNA.

As used herein, “sense strand” refers to a single stranded nucleic acidmolecule which has a sequence complementary to that of an antisensestrand. When the antisense strand contains modified nucleotides withbase analogs, the sense strand need not be complementary over the entirelength of the antisense strand, but must at least duplex with theantisense strand.

As used herein, “guide strand” refers to a single stranded nucleic acidmolecule of a dsRNA or dsRNA-containing molecule, which has a sequencesufficiently complementary to that of a target RNA to result in RNAinterference. After cleavage of the dsRNA or dsRNA-containing moleculeby Dicer, a fragment of the guide strand remains associated with RISC,binds a target RNA as a component of the RISC complex, and promotescleavage of a target RNA by RISC. As used herein, the guide strand doesnot necessarily refer to a continuous single stranded nucleic acid andmay comprise a discontinuity, preferably at a site that is cleaved byDicer. A guide strand is an antisense strand.

As used herein, “passenger strand” refers to an oligonucleotide strandof a dsRNA or dsRNA-containing molecule, which has a sequence that iscomplementary to that of the guide strand. As used herein, the passengerstrand does not necessarily refer to a continuous single strandednucleic acid and may comprise a discontinuity, preferably at a site thatis cleaved by Dicer. A passenger strand is a sense strand.

By “target nucleic acid” is meant a nucleic acid sequence whoseexpression, level or activity is to be modulated. The target nucleicacid can be DNA or RNA. For agents that target HIF-1α, in certainembodiments, the target nucleic acid is HIF-1α RNA. HIF-1α RNA targetsites can also interchangeably be referenced by corresponding cDNAsequences. Levels of HIF-1α may also be targeted via targeting ofupstream effectors of HIF-1α, or the effects of modulated ormisregulated HIF-1α may also be modulated by targeting of moleculesdownstream of HIF-1α in the HIF-1α signalling pathway.

By “complementarity” is meant that a nucleic acid can form hydrogenbond(s) with another nucleic acid sequence by either traditionalWatson-Crick or other non-traditional types. In reference to the nucleicmolecules of the present invention, the binding free energy for anucleic acid molecule with its complementary sequence is sufficient toallow the relevant function of the nucleic acid to proceed, e.g., RNAiactivity. Determination of binding free energies for nucleic acidmolecules is well known in the art (see, e.g., Turner et al., 1987, CSHSymp. Quant. Biol. LII pp. 123-133; Frier et al., 1986, Proc. Nat. Acad.Sci. USA 83:9373-9377; Turner et al., 1987, J. Am. Chem. Soc.109:3783-3785). A percent complementarity indicates the percentage ofcontiguous residues in a nucleic acid molecule that can form hydrogenbonds (e.g., Watson-Crick base pairing) with a second nucleic acidsequence (e.g., 5, 6, 7, 8, 9, or 10 nucleotides out of a total of 10nucleotides in the first oligonucleotide being based paired to a secondnucleic acid sequence having 10 nucleotides represents 50%, 60%, 70%,80%, 90%, and 100% complementary respectively). “Perfectlycomplementary” means that all the contiguous residues of a nucleic acidsequence will hydrogen bond with the same number of contiguous residuesin a second nucleic acid sequence. In one embodiment, a dsRNA moleculeof the invention comprises 19 to 30 (e.g., 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, or 30 or more) nucleotides that are complementary to oneor more target nucleic acid molecules or a portion thereof.

In one embodiment, dsRNA molecules of the invention that down regulateor reduce HIF-1α gene expression are used for treating, preventing orreducing HIF-1α-related diseases or disorders (e.g., cancer) in asubject or organism.

In one embodiment of the present invention, each sequence of a DsiRNAmolecule of the invention is independently 25 to 35 nucleotides inlength, in specific embodiments 25, 26, 27, 28, 29, 30, 31, 32, 33, 34or 35 nucleotides in length. In another embodiment, the DsiRNA duplexesof the invention independently comprise 25 to 30 base pairs (e.g., 25,26, 27, 28, 29, or 30). In another embodiment, one or more strands ofthe DsiRNA molecule of the invention independently comprises 19 to 35nucleotides (e.g., 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34 or 35) that are complementary to a target (HIF-1α) nucleicacid molecule. In certain embodiments, a DsiRNA molecule of theinvention possesses a length of duplexed nucleotides between 25 and 34nucleotides in length (e.g., 25, 26, 27, 28, 29, 30, 31, 32, 33 or 34nucleotides in length; optionally, all such nucleotides base pair withcognate nucleotides of the opposite strand). (Exemplary DsiRNA moleculesof the invention are shown in FIG. 1, and below.

As used herein “cell” is used in its usual biological sense, and doesnot refer to an entire multicellular organism, e.g., specifically doesnot refer to a human. The cell can be present in an organism, e.g.,birds, plants and mammals such as humans, cows, sheep, apes, monkeys,swine, dogs, and cats. The cell can be prokaryotic (e.g., bacterialcell) or eukaryotic (e.g., mammalian or plant cell). The cell can be ofsomatic or germ line origin, totipotent or pluripotent, dividing ornon-dividing. The cell can also be derived from or can comprise a gameteor embryo, a stem cell, or a fully differentiated cell. Within certainaspects, the term “cell” refers specifically to mammalian cells, such ashuman cells, that contain one or more isolated dsRNA molecules of thepresent disclosure. In particular aspects, a cell processes dsRNAs ordsRNA-containing molecules resulting in RNA interference of targetnucleic acids, and contains proteins and protein complexes required forRNAi, e.g., Dicer and RISC.

In certain embodiments, dsRNAs of the invention are Dicer substratesiRNAs (“DsiRNAs”). DsiRNAs can possess certain advantages as comparedto inhibitory nucleic acids that are not dicer substrates(“non-DsiRNAs”). Such advantages include, but are not limited to,enhanced duration of effect of a DsiRNA relative to a non-DsiRNA, aswell as enhanced inhibitory activity of a DsiRNA as compared to anon-DsiRNA (e.g., a 19-23mer siRNA) when each inhibitory nucleic acid issuitably formulated and assessed for inhibitory activity in a mammaliancell at the same concentration (in this latter scenario, the DsiRNAwould be identified as more potent than the non-DsiRNA). Detection ofthe enhanced potency of a DsiRNA relative to a non-DsiRNA is often mostreadily achieved at a formulated concentration (e.g., transfectionconcentration of the dsRNA) that results in the DsiRNA elicitingapproximately 30-70% knockdown activity upon a target RNA (e.g., amRNA). For active DsiRNAs, such levels of knockdown activity are mostoften achieved at in vitro mammalian cell DsiRNA transfectionconcentrations of 1 nM or less of as suitably formulated, and in certaininstances are observed at DsiRNA transfection concentrations of 200 pMor less, 100 pM or less, 50 pM or less, 20 pM or less, 10 pM or less, 5pM or less, or even 1 pM or less. Indeed, due to the variability amongDsiRNAs of the precise concentration at which 30-70% knockdown of atarget RNA is observed, construction of an IC50 curve via assessment ofthe inhibitory activity of DsiRNAs and non-DsiRNAs across a range ofeffective concentrations is a preferred method for detecting theenhanced potency of a DsiRNA relative to a non-DsiRNA inhibitory agent.

In certain embodiments, a DsiRNA (in a state as initially formed, priorto dicer cleavage) is more potent at reducing HIF-1α target geneexpression in a mammalian cell than a 19, 20, 21, 22 or 23 base pairsequence that is contained within it. In certain such embodiments, aDsiRNA prior to dicer cleavage is more potent than a 19-21mer containedwithin it. Optionally, a DsiRNA prior to dicer cleavage is more potentthan a 19 base pair duplex contained within it that is synthesized withsymmetric dTdT overhangs (thereby forming a siRNA possessing 21nucleotide strand lengths having dTdT overhangs). In certainembodiments, the DsiRNA is more potent than a 19-23mer siRNA (e.g., a 19base pair duplex with dTdT overhangs) that targets at least 19nucleotides of the 21 nucleotide target sequence that is recited for aDsiRNA of the invention (without wishing to be bound by theory, theidentity of a such a target site for a DsiRNA is identified viaidentification of the Ago2 cleavage site for the DsiRNA; once the Ago2cleavage site of a DsiRNA is determined for a DsiRNA, identification ofthe Ago2 cleavage site for any other inhibitory dsRNA can be performedand these Ago2 cleavage sites can be aligned, thereby determining thealignment of projected target nucleotide sequences for multiple dsRNAs).In certain related embodiments, the DsiRNA is more potent than a19-23mer siRNA that targets at least 20 nucleotides of the 21 nucleotidetarget sequence that is recited for a DsiRNA of the invention.Optionally, the DsiRNA is more potent than a 19-23mer siRNA that targetsthe same 21 nucleotide target sequence that is recited for a DsiRNA ofthe invention. In certain embodiments, the DsiRNA is more potent thanany 21mer siRNA that targets the same 21 nucleotide target sequence thatis recited for a DsiRNA of the invention. Optionally, the DsiRNA is morepotent than any 21 or 22mer siRNA that targets the same 21 nucleotidetarget sequence that is recited for a DsiRNA of the invention. Incertain embodiments, the DsiRNA is more potent than any 21, 22 or 23mersiRNA that targets the same 21 nucleotide target sequence that isrecited for a DsiRNA of the invention. As noted above, such potencyassessments are most effectively performed upon dsRNAs that are suitablyformulated (e.g., formulated with an appropriate transfection reagent)at a concentration of 1 nM or less. Optionally, an IC50 assessment isperformed to evaluate activity across a range of effective inhibitoryconcentrations, thereby allowing for robust comparison of the relativepotencies of dsRNAs so assayed.

The dsRNA molecules of the invention are added directly, or can becomplexed with lipids (e.g., cationic lipids), packaged withinliposomes, or otherwise delivered to target cells or tissues. Thenucleic acid or nucleic acid complexes can be locally administered torelevant tissues ex vivo, or in vivo through direct dermal application,transdermal application, or injection, with or without theirincorporation in biopolymers. In particular embodiments, the nucleicacid molecules of the invention comprise sequences shown in FIG. 1, andthe below exemplary structures. Examples of such nucleic acid moleculesconsist essentially of sequences defined in these figures and exemplarystructures. Furthermore, where such agents are modified in accordancewith the below description of modification patterning of DsiRNA agents,chemically modified forms of constructs described in FIG. 1, and thebelow exemplary structures can be used in all uses described for theDsiRNA agents of FIG. 1, and the below exemplary structures.

In another aspect, the invention provides mammalian cells containing oneor more dsRNA molecules of this invention. The one or more dsRNAmolecules can independently be targeted to the same or different sites.

By “RNA” is meant a molecule comprising at least one, and preferably atleast 4, 8 and 12 ribonucleotide residues. The at least 4, 8 or 12 RNAresidues may be contiguous. By “ribonucleotide” is meant a nucleotidewith a hydroxyl group at the 2′ position of a β-D-ribofuranose moiety.The terms include double-stranded RNA, single-stranded RNA, isolated RNAsuch as partially purified RNA, essentially pure RNA, synthetic RNA,recombinantly produced RNA, as well as altered RNA that differs fromnaturally occurring RNA by the addition, deletion, substitution and/oralteration of one or more nucleotides. Such alterations can includeaddition of non-nucleotide material, such as to the end(s) of the dsRNAor internally, for example at one or more nucleotides of the RNA.Nucleotides in the RNA molecules of the instant invention can alsocomprise non-standard nucleotides, such as non-naturally occurringnucleotides or chemically synthesized nucleotides or deoxynucleotides.These altered RNAs can be referred to as analogs or analogs ofnaturally-occurring RNA.

By “subject” is meant an organism, which is a donor or recipient ofexplanted cells or the cells themselves. “Subject” also refers to anorganism to which the dsRNA agents of the invention can be administered.A subject can be a mammal or mammalian cells, including a human or humancells.

The phrase “pharmaceutically acceptable carrier” refers to a carrier forthe administration of a therapeutic agent. Exemplary carriers includesaline, buffered saline, dextrose, water, glycerol, ethanol, andcombinations thereof. For drugs administered orally, pharmaceuticallyacceptable carriers include, but are not limited to pharmaceuticallyacceptable excipients such as inert diluents, disintegrating agents,binding agents, lubricating agents, sweetening agents, flavoring agents,coloring agents and preservatives. Suitable inert diluents includesodium and calcium carbonate, sodium and calcium phosphate, and lactose,while corn starch and alginic acid are suitable disintegrating agents.Binding agents may include starch and gelatin, while the lubricatingagent, if present, will generally be magnesium stearate, stearic acid ortalc. If desired, the tablets may be coated with a material such asglyceryl monostearate or glyceryl distearate, to delay absorption in thegastrointestinal tract. The pharmaceutically acceptable carrier of thedisclosed dsRNA compositions may be micellar structures, such as aliposomes, capsids, capsoids, polymeric nanocapsules, or polymericmicrocapsules.

Polymeric nanocapsules or microcapsules facilitate transport and releaseof the encapsulated or bound dsRNA into the cell. They include polymericand monomeric materials, especially including polybutylcyanoacrylate. Asummary of materials and fabrication methods has been published (seeKreuter, 1991). The polymeric materials which are formed from monomericand/or oligomeric precursors in the polymerization/nanoparticlegeneration step, are per se known from the prior art, as are themolecular weights and molecular weight distribution of the polymericmaterial which a person skilled in the field of manufacturingnanoparticles may suitably select in accordance with the usual skill.

Various methodologies of the instant invention include step thatinvolves comparing a value, level, feature, characteristic, property,etc. to a “suitable control”, referred to interchangeably herein as an“appropriate control”. A “suitable control” or “appropriate control” isa control or standard familiar to one of ordinary skill in the artuseful for comparison purposes. In one embodiment, a “suitable control”or “appropriate control” is a value, level, feature, characteristic,property, etc. determined prior to performing an RNAi methodology, asdescribed herein. For example, a transcription rate, mRNA level,translation rate, protein level, biological activity, cellularcharacteristic or property, genotype, phenotype, etc. can be determinedprior to introducing an RNA silencing agent (e.g., DsiRNA) of theinvention into a cell or organism. In another embodiment, a “suitablecontrol” or “appropriate control” is a value, level, feature,characteristic, property, etc. determined in a cell or organism, e.g., acontrol or normal cell or organism, exhibiting, for example, normaltraits. In yet another embodiment, a “suitable control” or “appropriatecontrol” is a predefined value, level, feature, characteristic,property, etc.

The term “in vitro” has its art recognized meaning, e.g., involvingpurified reagents or extracts, e.g., cell extracts. The term “in vivo”also has its art recognized meaning, e.g., involving living cells, e.g.,immortalized cells, primary cells, cell lines, and/or cells in anorganism.

“Treatment”, or “treating” as used herein, is defined as the applicationor administration of a therapeutic agent (e.g., a dsRNA agent or avector or transgene encoding same) to a patient, or application oradministration of a therapeutic agent to an isolated tissue or cell linefrom a patient, who has a disorder with the purpose to cure, heal,alleviate, relieve, alter, remedy, ameliorate, improve or affect thedisease or disorder, or symptoms of the disease or disorder. The term“treatment” or “treating” is also used herein in the context ofadministering agents prophylactically. The term “effective dose” or“effective dosage” is defined as an amount sufficient to achieve or atleast partially achieve the desired effect. The term “therapeuticallyeffective dose” is defined as an amount sufficient to cure or at leastpartially arrest the disease and its complications in a patient alreadysuffering from the disease. The term “patient” includes human and othermammalian subjects that receive either prophylactic or therapeutictreatment.

Structures of Anti-HIF-1α DsiRNA Agents

In certain embodiments, the anti-HIF-1α DsiRNA agents of the inventioncan have the following structures:

In one such embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “Y” is an overhang domain comprised of 1-4 RNAmonomers that are optionally 2′-O-methyl RNA monomers. In a relatedembodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “Y” is an overhang domain comprised of 1-4 RNA monomersthat are optionally 2′-O-methyl RNA monomers, and “D”=DNA. In oneembodiment, the top strand is the sense strand, and the bottom strand isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand.

DsiRNAs of the invention can carry a broad range of modificationpatterns (e.g., 2′-O-methyl RNA patterns, e.g., within extended DsiRNAagents). Certain modification patterns of the second strand of DsiRNAsof the invention are presented below.

In one embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. In arelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers, and“D”=DNA. The top strand is the sense strand, and the bottom strand isthe antisense strand.

In another such embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. In arelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand.

In another such embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. In arelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. In arelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. In a further relatedembodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M7” or “M7”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. In arelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. The top strand is the sense strand, and the bottomstrand is the antisense strand. In another related embodiment, theDsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M6” or “M6”modification pattern.

In other embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In a related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In anotherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M5” or “M5”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In a related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M4” or “M4”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In a related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M8” or “M8”modification pattern.

In other embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M3” or “M3”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In a related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M2” or “M2”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In a related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M1” or “M1”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M9” or “M9”modification pattern.

In other embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In a related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M10” or “M10”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M11” or “M11”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M12” or “M12”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M13” or “M13”modification pattern.

In other embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M21” or “M21”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M14” or “M14”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M15” or “M15”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In a related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M16” or “M16”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M17” or “M17”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M18” or “M18”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M19” or “M19”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M20” or “M20”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M22” or “M22”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M24” or “M24”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M25” or “M25”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M26” or “M26”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M27” or “M27”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M28” or “M28”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M29” or “M29”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M30” or “M30”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M31” or “M31”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M32” or “M32”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M34” or “M34”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M35” or “M35”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M37” or “M37”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M38” or “M38”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M40” or “M40”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers and underlined residues are 2′-O-methyl RNA monomers. The topstrand is the sense strand, and the bottom strand is the antisensestrand. In one related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M41” or “M41”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. In a further relatedembodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M7*” or “M7*”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M6*” or “M6*”modification pattern.

In other embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In anotherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M5*” or “M5*”modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M4*” or “M4*”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M8*” or “M8*”modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M2*” or “M2*”modification pattern.

In other embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M10*” or“M10*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M11*” or“M11*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M13*” or“M13*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M14*” or“M14*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M15*” or“M15*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M16*” or“M16*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M17*” or“M17*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M18*” or“M18*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M19*” or“M19*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-YXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an overhang domaincomprised of 1-4 RNA monomers that are optionally 2′-O-methyl RNAmonomers, underlined residues are 2′-O-methyl RNA monomers, and “D”=DNA.The top strand is the sense strand, and the bottom strand is theantisense strand. In another related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M20*” or“M20*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M22*” or“M22*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M24*” or“M24*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M25*” or“M25*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M26*” or“M26*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M27*” or“M27*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M28*” or“M28*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M29*” or“M29*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M34*” or“M34*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M35*” or“M35*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M37*” or“M37*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M38*” or“M38*” modification pattern.

In further embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M40*” or“M40*” modification pattern.

In additional embodiments, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA and “X”=2′-O-methyl RNA. The top strand is the sensestrand, and the bottom strand is the antisense strand. In a furtherrelated embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ 3′-XXXXXXXXXXXXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA. The top strand is thesense strand, and the bottom strand is the antisense strand. Thismodification pattern is also referred to herein as the “AS-M41*” or“M41*” modification pattern.

In certain embodiments, the sense strand of a DsiRNA of the invention ismodified—specific exemplary forms of sense strand modifications areshown below, and it is contemplated that such modified sense strands canbe substituted for the sense strand of any of the DsiRNAs shown above togenerate a DsiRNA comprising a below-depicted sense strand that annealswith an above-depicted antisense strand. Exemplary sense strandmodification patterns include:

5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM1” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM2” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM3”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM4” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM5” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM6”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM7” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM8” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM9”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM10” 5′-XXXXXXXXXXXXXXXXXXXXXXX DD-3′“SM11” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM12”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM13” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′“SM14” 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM15”5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ “SM16” 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′ 5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′5′-XXXXXXXXXXXXXXXXXXXXXXXXX-3′where “X”=RNA, “X”=2′-O-methyl RNA, and “D”=DNA.

The above modification patterns can also be incorporated into, e.g., theextended DsiRNA structures and mismatch and/or frayed DsiRNA structuresdescribed below.

In another embodiment, the DsiRNA comprises strands having equal lengthspossessing 1-3 mismatched residues that serve to orient Dicer cleavage(specifically, one or more of positions 1, 2 or 3 on the first strand ofthe DsiRNA, when numbering from the 3′-terminal residue, are mismatchedwith corresponding residues of the 5′-terminal region on the secondstrand when first and second strands are annealed to one another). Anexemplary 27mer DsiRNA agent with two terminal mismatched residues isshown:

wherein “X”=RNA, “M”=Nucleic acid residues (RNA, DNA or non-natural ormodified nucleic acids) that do not base pair (hydrogen bond) withcorresponding “M” residues of otherwise complementary strand whenstrands are annealed. Any of the residues of such agents can optionallybe 2′-O-methyl RNA monomers—alternating positioning of 2′-O-methyl RNAmonomers that commences from the 3′-terminal residue of the bottom(second) strand, as shown for above asymmetric agents, can also be usedin the above “blunt/fray” DsiRNA agent. In one embodiment, the topstrand is the sense strand, and the bottom strand is the antisensestrand. Alternatively, the bottom strand is the sense strand and the topstrand is the antisense strand.

In certain additional embodiments, the present invention providescompositions for RNA interference (RNAi) that possess one or more basepaired deoxyribonucleotides within a region of a double strandedribonucleic acid (dsRNA) that is positioned 3′ of a projected sensestrand Dicer cleavage site and correspondingly 5′ of a projectedantisense strand Dicer cleavage site. The compositions of the inventioncomprise a dsRNA which is a precursor molecule, i.e., the dsRNA of thepresent invention is processed in vivo to produce an active smallinterfering nucleic acid (siRNA). The dsRNA is processed by Dicer to anactive siRNA which is incorporated into RISC.

In certain embodiments, the DsiRNA agents of the invention can have thefollowing exemplary structures (noting that any of the followingexemplary structures can be combined, e.g., with the bottom strandmodification patterns of the above-described structures—in one specificexample, the bottom strand modification pattern shown in any of theabove structures is applied to the 27 most 3′ residues of the bottomstrand of any of the following structures; in another specific example,the bottom strand modification pattern shown in any of the abovestructures upon the 23 most 3′ residues of the bottom strand is appliedto the 23 most 3′ residues of the bottom strand of any of the followingstructures):

In one such embodiment, the DsiRNA comprises the following (an exemplary“right-extended”, “DNA extended” DsiRNA):

5′-XXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)DD-3′3′-YXXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)XX-5′wherein “X”=RNA, “Y” is an optional overhang domain comprised of 0-10RNA monomers that are optionally 2′-O-methyl RNA monomers—in certainembodiments, “Y” is an overhang domain comprised of 1-4 RNA monomersthat are optionally 2′-O-methyl RNA monomers, “D”=DNA, and “N”=1 to 50or more, but is optionally 1-8 or 1-10. “N*”=0 to 15 or more, but isoptionally 0, 1, 2, 3, 4, 5 or 6. In one embodiment, the top strand isthe sense strand, and the bottom strand is the antisense strand.Alternatively, the bottom strand is the sense strand and the top strandis the antisense strand.

In a related embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)DD-3′3′-YXXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)DD-5′wherein “X”=RNA, “Y” is an optional overhang domain comprised of 0-10RNA monomers that are optionally 2′-O-methyl RNA monomers—in certainembodiments, “Y” is an overhang domain comprised of 1-4 RNA monomersthat are optionally 2′-O-methyl RNA monomers, “D”=DNA, and “N”=1 to 50or more, but is optionally 1-8 or 1-10. “N*”=0 to 15 or more, but isoptionally 0, 1, 2, 3, 4, 5 or 6. In one embodiment, the top strand isthe sense strand, and the bottom strand is the antisense strand.Alternatively, the bottom strand is the sense strand and the top strandis the antisense strand.

In an additional embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)DD-3′3′-YXXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)ZZ-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an optional overhang domaincomprised of 0-10 RNA monomers that are optionally 2′-O-methyl RNAmonomers—in certain embodiments, “Y” is an overhang domain comprised of1-4 RNA monomers that are optionally 2′-O-methyl RNA monomers, “D”=DNA,“Z”=DNA or RNA, and “N”=1 to 50 or more, but is optionally 1-8 or 1-10.“N*”=0 to 15 or more, but is optionally 0, 1, 2, 3, 4, 5 or 6. In oneembodiment, the top strand is the sense strand, and the bottom strand isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand, with 2′-O-methyl RNAmonomers located at alternating residues along the top strand, ratherthan the bottom strand presently depicted in the above schematic.

In another such embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)DD-3′3′-YXXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)ZZ-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an optional overhang domaincomprised of 0-10 RNA monomers that are optionally 2′-O-methyl RNAmonomers—in certain embodiments, “Y” is an overhang domain comprised of1-4 RNA monomers that are optionally 2′-O-methyl RNA monomers, “D”=DNA,“Z”=DNA or RNA, and “N”=1 to 50 or more, but is optionally 1-8 or 1-10.“N*”=0 to 15 or more, but is optionally 0, 1, 2, 3, 4, 5 or 6. In oneembodiment, the top strand is the sense strand, and the bottom strand isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand, with 2′-O-methyl RNAmonomers located at alternating residues along the top strand, ratherthan the bottom strand presently depicted in the above schematic.

In another such embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)DD-3′3′-YXXXXXXXXXXXXXXXXXXXXXXXX_(N*)D_(N)ZZ-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “Y” is an optional overhang domaincomprised of 0-10 RNA monomers that are optionally 2′-O-methyl RNAmonomers—in certain embodiments, “Y” is an overhang domain comprised of1-4 RNA monomers that are optionally 2′-O-methyl RNA monomers, “D”=DNA,“Z”=DNA or RNA, and “N”=1 to 50 or more, but is optionally 1-8 or 1-10.“N*”=0 to 15 or more, but is optionally 0, 1, 2, 3, 4, 5 or 6. In oneembodiment, the top strand is the sense strand, and the bottom strand isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand, with 2′-O-methyl RNAmonomers located at alternating residues along the top strand, ratherthan the bottom strand presently depicted in the above schematic.

In another embodiment, the DsiRNA comprises:

5′-XXXXXXXXXXXXXXXXXXXXXXXX_(N*)[X1/D1]_(N)DD-3′3′-YXXXXXXXXXXXXXXXXXXXXXXXX_(N*)[X2/D2]_(N)ZZ-5′wherein “X”=RNA, “Y” is an optional overhang domain comprised of 0-10RNA monomers that are optionally 2′-O-methyl RNA monomers—in certainembodiments, “Y” is an overhang domain comprised of 1-4 RNA monomersthat are optionally 2′-O-methyl RNA monomers, “D”=DNA, “Z”=DNA or RNA,and “N”=1 to 50 or more, but is optionally 1-8 or 1-10, where at leastone D1_(N) is present in the top strand and is base paired with acorresponding D2_(N) in the bottom strand. Optionally, D1_(N) andD1_(NA) are base paired with corresponding D2_(N) and D2_(N+1); D1_(N),D1_(N+1) and D1_(N+2) are base paired with corresponding D2_(N),D1_(N+1) and D1_(N+2), etc. “N*”=0 to 15 or more, but is optionally 0,1, 2, 3, 4, 5 or 6. In one embodiment, the top strand is the sensestrand, and the bottom strand is the antisense strand. Alternatively,the bottom strand is the sense strand and the top strand is theantisense strand, with 2′-O-methyl RNA monomers located at alternatingresidues along the top strand, rather than the bottom strand presentlydepicted in the above schematic.

In the structures depicted herein, the 5′ end of either the sense strandor antisense strand can optionally comprise a phosphate group.

In another embodiment, a DNA:DNA-extended DsiRNA comprises strandshaving equal lengths possessing 1-3 mismatched residues that serve toorient Dicer cleavage (specifically, one or more of positions 1, 2 or 3on the first strand of the DsiRNA, when numbering from the 3′-terminalresidue, are mismatched with corresponding residues of the 5′-terminalregion on the second strand when first and second strands are annealedto one another). An exemplary DNA:DNA-extended DsiRNA agent with twoterminal mismatched residues is shown:

wherein “X”=RNA, “M”=Nucleic acid residues (RNA, DNA or non-natural ormodified nucleic acids) that do not base pair (hydrogen bond) withcorresponding “M” residues of otherwise complementary strand whenstrands are annealed, “D”=DNA and “N”=1 to 50 or more, but is optionally1-15 or, optionally, 1-8. “N*”=0 to 15 or more, but is optionally 0, 1,2, 3, 4, 5 or 6. Any of the residues of such agents can optionally be2′-O-methyl RNA monomers—alternating positioning of 2′-O-methyl RNAmonomers that commences from the 3′-terminal residue of the bottom(second) strand, as shown for above asymmetric agents, can also be usedin the above “blunt/fray” DsiRNA agent. In one embodiment, the topstrand (first strand) is the sense strand, and the bottom strand (secondstrand) is the antisense strand. Alternatively, the bottom strand is thesense strand and the top strand is the antisense strand. Modificationand DNA:DNA extension patterns paralleling those shown above forasymmetric/overhang agents can also be incorporated into such“blunt/frayed” agents.

In one embodiment, a length-extended DsiRNA agent is provided thatcomprises deoxyribonucleotides positioned at sites modeled to functionvia specific direction of Dicer cleavage, yet which does not require thepresence of a base-paired deoxyribonucleotide in the dsRNA structure. Anexemplary structure for such a molecule is shown:

5′-XXXXXXXXXXXXXXXXXXXDDXX-3′ 3′-YXXXXXXXXXXXXXXXXXDDXXXX-5′wherein “X”=RNA, “Y” is an optional overhang domain comprised of 0-10RNA monomers that are optionally 2′-O-methyl RNA monomers—in certainembodiments, “Y” is an overhang domain comprised of 1-4 RNA monomersthat are optionally 2′-O-methyl RNA monomers, and “D”=DNA. In oneembodiment, the top strand is the sense strand, and the bottom strand isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand. The above structureis modeled to force Dicer to cleave a minimum of a 21mer duplex as itsprimary post-processing form. In embodiments where the bottom strand ofthe above structure is the antisense strand, the positioning of twodeoxyribonucleotide residues at the ultimate and penultimate residues ofthe 5′ end of the antisense strand will help reduce off-target effects(as prior studies have shown a 2′-O-methyl modification of at least thepenultimate position from the 5′ terminus of the antisense strand toreduce off-target effects; see, e.g., US 2007/0223427).

In one embodiment, the DsiRNA comprises the following (an exemplary“left-extended”, “DNA extended” DsiRNA):

5′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)Y-3′3′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)-5′wherein “X”=RNA, “Y” is an optional overhang domain comprised of 0-10RNA monomers that are optionally 2′-O-methyl RNA monomers—in certainembodiments, “Y” is an overhang domain comprised of 1-4 RNA monomersthat are optionally 2′-O-methyl RNA monomers, “D”=DNA, and “N”=1 to 50or more, but is optionally 1-8 or 1-10. “N*”=0 to 15 or more, but isoptionally 0, 1, 2, 3, 4, 5 or 6. In one embodiment, the top strand isthe sense strand, and the bottom strand is the antisense strand.Alternatively, the bottom strand is the sense strand and the top strandis the antisense strand.

In a related embodiment, the DsiRNA comprises:

5′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)DD-3′3′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)XX-5′wherein “X”=RNA, optionally a 2′-O-methyl RNA monomers “D”=DNA, “N”=1 to50 or more, but is optionally 1-8 or 1-10. “N*”=0 to 15 or more, but isoptionally 0, 1, 2, 3, 4, 5 or 6. In one embodiment, the top strand isthe sense strand, and the bottom strand is the antisense strand.Alternatively, the bottom strand is the sense strand and the top strandis the antisense strand.

In an additional embodiment, the DsiRNA comprises:

5′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)DD-3′ 3′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)ZZ-5′wherein “X”=RNA, optionally a 2′-O-methyl RNA monomers “D”=DNA, “N”=1 to50 or more, but is optionally 1-8 or 1-10. “N*”=0 to 15 or more, but isoptionally 0, 1, 2, 3, 4, 5 or 6. “Z”=DNA or RNA. In one embodiment, thetop strand is the sense strand, and the bottom strand is the antisensestrand. Alternatively, the bottom strand is the sense strand and the topstrand is the antisense strand, with 2′-O-methyl RNA monomers located atalternating residues along the top strand, rather than the bottom strandpresently depicted in the above schematic.

In another such embodiment, the DsiRNA comprises:

5′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)DD-3′ 3′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)ZZ-5′wherein “X”=RNA, optionally a 2′-O-methyl RNA monomers “D”=DNA, “N”=1 to50 or more, but is optionally 1-8 or 1-10. “N*”=0 to 15 or more, but isoptionally 0, 1, 2, 3, 4, 5 or 6. “Z”=DNA or RNA. In one embodiment, thetop strand is the sense strand, and the bottom strand is the antisensestrand. Alternatively, the bottom strand is the sense strand and the topstrand is the antisense strand, with 2′-O-methyl RNA monomers located atalternating residues along the top strand, rather than the bottom strandpresently depicted in the above schematic.

In another such embodiment, the DsiRNA comprises:

5′-D_(N)ZZXXXXXXXXXXXXXXXXXXXXXXXX_(N*)DD-3′ 3′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXXXX_(N*)ZZ-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “D”=DNA, “Z”=DNA or RNA, and “N”=1to 50 or more, but is optionally 1-8 or 1-10. “N*”=0 to 15 or more, butis optionally 0, 1, 2, 3, 4, 5 or 6. In one embodiment, the top strandis the sense strand, and the bottom strand is the antisense strand.Alternatively, the bottom strand is the sense strand and the top strandis the antisense strand, with 2′-O-methyl RNA monomers located atalternating residues along the top strand, rather than the bottom strandpresently depicted in the above schematic.

In another such embodiment, the DsiRNA comprises:

5′-D_(N)ZZXXXXXXXXXXXXXXXXXXXXXXXX_(N*)Y-3′ 3′-D_(N)XXXXXXXXXXXXXXXXXXXXXXXXXX_(N*)-5′wherein “X”=RNA, “X”=2′-O-methyl RNA, “D”=DNA, “Z”=DNA or RNA, and “N”=1to 50 or more, but is optionally 1-8 or 1-10. “N*”=0 to 15 or more, butis optionally 0, 1, 2, 3, 4, 5 or 6. “Y” is an optional overhang domaincomprised of 0-10 RNA monomers that are optionally 2′-O-methyl RNAmonomers—in certain embodiments, “Y” is an overhang domain comprised of1-4 RNA monomers that are optionally 2′-O-methyl RNA monomers. In oneembodiment, the top strand is the sense strand, and the bottom strand isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand, with 2′-O-methyl RNAmonomers located at alternating residues along the top strand, ratherthan the bottom strand presently depicted in the above schematic.

In another embodiment, the DsiRNA comprises:

5′-[X1/D1]_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)DD-3′3′-[X2/D2]_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)ZZ-5′wherein “X”=RNA, “D”=DNA, “Z”=DNA or RNA, and “N”=1 to 50 or more, butis optionally 1-8 or 1-10, where at least one D1_(N) is present in thetop strand and is base paired with a corresponding D2_(N) in the bottomstrand. Optionally, D1_(N) and D1_(NA) are base paired withcorresponding D2_(N) and D2_(N+1); D1_(N), D1_(NA) and D1_(N+2) are basepaired with corresponding D2_(N), D1_(NA) and D1_(N+2), etc. “N*”=0 to15 or more, but is optionally 0, 1, 2, 3, 4, 5 or 6. In one embodiment,the top strand is the sense strand, and the bottom strand is theantisense strand. Alternatively, the bottom strand is the sense strandand the top strand is the antisense strand, with 2′-O-methyl RNAmonomers located at alternating residues along the top strand, ratherthan the bottom strand presently depicted in the above schematic.

In a related embodiment, the DsiRNA comprises:

5′-[X1/D1]_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)Y-3′3′-[X2/D2]_(N)XXXXXXXXXXXXXXXXXXXXXXXX_(N*)-5′wherein “X”=RNA, “D”=DNA, “Y” is an optional overhang domain comprisedof 0-10 RNA monomers that are optionally 2′-O-methyl RNA monomers—incertain embodiments, “Y” is an overhang domain comprised of 1-4 RNAmonomers that are optionally 2′-O-methyl RNA monomers, and “N”=1 to 50or more, but is optionally 1-8 or 1-10, where at least one D1_(N) ispresent in the top strand and is base paired with a corresponding D2_(N)in the bottom strand. Optionally, D1_(N) and D1_(NA) are base pairedwith corresponding D2_(N) and D2_(N+1); D1_(N), D1_(NA) and D1_(N+2) arebase paired with corresponding D2_(N), D1_(NA) and D1_(N+2), etc. “N*”=0to 15 or more, but is optionally 0, 1, 2, 3, 4, 5 or 6. In oneembodiment, the top strand is the sense strand, and the bottom strand isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand, with 2′-O-methyl RNAmonomers located at alternating residues along the top strand, ratherthan the bottom strand presently depicted in the above schematic.

In another embodiment, the DNA:DNA-extended DsiRNA comprises strandshaving equal lengths possessing 1-3 mismatched residues that serve toorient Dicer cleavage (specifically, one or more of positions 1, 2 or 3on the first strand of the DsiRNA, when numbering from the 3′-terminalresidue, are mismatched with corresponding residues of the 5′-terminalregion on the second strand when first and second strands are annealedto one another). An exemplary DNA:DNA-extended DsiRNA agent with twoterminal mismatched residues is shown:

wherein “X”=RNA, “M”=Nucleic acid residues (RNA, DNA or non-natural ormodified nucleic acids) that do not base pair (hydrogen bond) withcorresponding “M” residues of otherwise complementary strand whenstrands are annealed, “D”=DNA and “N”=1 to 50 or more, but is optionally1-8 or 1-10. “N*”=0 to 15 or more, but is optionally 0, 1, 2, 3, 4, 5 or6. Any of the residues of such agents can optionally be 2′-O-methyl RNAmonomers—alternating positioning of 2′-O-methyl RNA monomers thatcommences from the 3′-terminal residue of the bottom (second) strand, asshown for above asymmetric agents, can also be used in the above“blunt/fray” DsiRNA agent. In one embodiment, the top strand (firststrand) is the sense strand, and the bottom strand (second strand) isthe antisense strand. Alternatively, the bottom strand is the sensestrand and the top strand is the antisense strand. Modification andDNA:DNA extension patterns paralleling those shown above forasymmetric/overhang agents can also be incorporated into such“blunt/frayed” agents.

In another embodiment, a length-extended DsiRNA agent is provided thatcomprises deoxyribonucleotides positioned at sites modeled to functionvia specific direction of Dicer cleavage, yet which does not require thepresence of a base-paired deoxyribonucleotide in the dsRNA structure.Exemplary structures for such a molecule are shown:

5′-XXDDXXXXXXXXXXXXXXXXXXXX_(N*)Y-3′ 3′-DDXXXXXXXXXXXXXXXXXXXXXX_(N*)-5′or 5′-XDXDXXXXXXXXXXXXXXXXXXXX_(N*)Y-3′3′-DXDXXXXXXXXXXXXXXXXXXXXX_(N*)-5′wherein “X”=RNA, “Y” is an optional overhang domain comprised of 0-10RNA monomers that are optionally 2′-O-methyl RNA monomers—in certainembodiments, “Y” is an overhang domain comprised of 1-4 RNA monomersthat are optionally 2′-O-methyl RNA monomers, and “D”=DNA. “N*”=0 to 15or more, but is optionally 0, 1, 2, 3, 4, 5 or 6. In one embodiment, thetop strand is the sense strand, and the bottom strand is the antisensestrand. Alternatively, the bottom strand is the sense strand and the topstrand is the antisense strand.

In any of the above embodiments where the bottom strand of the abovestructure is the antisense strand, the positioning of twodeoxyribonucleotide residues at the ultimate and penultimate residues ofthe 5′ end of the antisense strand will help reduce off-target effects(as prior studies have shown a 2′-O-methyl modification of at least thepenultimate position from the 5′ terminus of the antisense strand toreduce off-target effects; see, e.g., US 2007/0223427).

In certain embodiments, the “D” residues of the above structures includeat least one PS-DNA or PS-RNA. Optionally, the “D” residues of the abovestructures include at least one modified nucleotide that inhibits Dicercleavage.

While the above-described “DNA-extended” DsiRNA agents can becategorized as either “left extended” or “right extended”, DsiRNA agentscomprising both left- and right-extended DNA-containing sequences withina single agent (e.g., both flanks surrounding a core dsRNA structure aredsDNA extensions) can also be generated and used in similar manner tothose described herein for “right-extended” and “left-extended” agents.

In some embodiments, the DsiRNA of the instant invention furthercomprises a linking moiety or domain that joins the sense and antisensestrands of a DNA:DNA-extended DsiRNA agent. Optionally, such a linkingmoiety domain joins the 3′ end of the sense strand and the 5′ end of theantisense strand. The linking moiety may be a chemical (non-nucleotide)linker, such as an oligomethylenediol linker, oligoethylene glycollinker, or other art-recognized linker moiety. Alternatively, the linkercan be a nucleotide linker, optionally including an extended loop and/ortetraloop.

In one embodiment, the DsiRNA agent has an asymmetric structure, withthe sense strand having a 25-base pair length, and the antisense strandhaving a 27-base pair length with a 1-4 base 3′-overhang (e.g., a onebase 3′-overhang, a two base 3′-overhang, a three base 3′-overhang or afour base 3′-overhang). In another embodiment, this DsiRNA agent has anasymmetric structure further containing 2 deoxynucleotides at the 3′ endof the sense strand.

In another embodiment, the DsiRNA agent has an asymmetric structure,with the antisense strand having a 25-base pair length, and the sensestrand having a 27-base pair length with a 1-4 base 3′-overhang (e.g., aone base 3′-overhang, a two base 3′-overhang, a three base 3′-overhangor a four base 3′-overhang). In another embodiment, this DsiRNA agenthas an asymmetric structure further containing 2 deoxyribonucleotides atthe 3′ end of the antisense strand.

Exemplary HIF-1α targeting DsiRNA agents of the invention, and theirassociated HIF-1α target sequences, include the following, presented inthe below series of tables:

Table Number:

(2) Selected Anti-HIF-1α DsiRNA Agents (Asymmetrics, HIF-1α);

(3) Selected Anti-HIF-1α DsiRNAs, Unmodified Duplexes (Asymmetrics,HIF-1α Variant 1);

(4) Selected Mouse Anti-HIF-1α DsiRNAs (Asymmetrics);

(5) DsiRNA Target Sequences (21mers) In HIF-1α;

(6) Selected Human Anti-HIF-1α “Blunt/Fray” DsiRNAs (HIF-1α Variant 1);

(7) Selected Human Anti-HIF-1α “Blunt/Blunt” DsiRNAs (HIF-1α Variant 1);

TABLE 2 Selected Anti-HIF-1α DsiRNA Agents (Asymmetrics, HIF-1α)5′-GCGCGCCCGAGCGCGCCUCCGCCct-3′ (SEQ ID NO: 379)3′-GGCGCGCGGGCUCGCGCGGAGGCGGGA-5′ (SEQ ID NO: 1) HIF-1α-81 Target:5′-CCGCGCGCCCGAGCGCGCCTCCGCCCT-3′ (SEQ ID NO: 757)5′-GCGCCCGAGCGCGCCUCCGCCCUtg-3′ (SEQ ID NO: 380)3′-CGCGCGGGCUCGCGCGGAGGCGGGAAC-5′ (SEQ ID NO: 2) HIF-1α-83 Target:5′-GCGCGCCCGAGCGCGCCTCCGCCCTTG-3′ (SEQ ID NO: 758)5′-GCCCGAGCGCGCCUCCGCCCUUGcc-3′ (SEQ ID NO: 381)3′-CGCGGGCUCGCGCGGAGGCGGGAACGG-5′ (SEQ ID NO: 3) HIF-1α-85 Target:5′-GCGCCCGAGCGCGCCTCCGCCCTTGCC-3′ (SEQ ID NO: 759)5′-CCGAGCGCGCCUCCGCCCUUGCCcg-3′ (SEQ ID NO: 382)3′-CGGGCUCGCGCGGAGGCGGGAACGGGC-5′ (SEQ ID NO: 4) HIF-1α-87 Target:5′-GCCCGAGCGCGCCTCCGCCCTTGCCCG-3′ (SEQ ID NO: 760)5′-GAGCGCGCCUCCGCCCUUGCCCGcc-3′ (SEQ ID NO: 383)3′-GGCUCGCGCGGAGGCGGGAACGGGCGG-5′ (SEQ ID NO: 5) HIF-1α-89 Target:5′-CCGAGCGCGCCTCCGCCCTTGCCCGCC-3′ (SEQ ID NO: 761)5′-UGCCUCAGCUCCUCAGUGCACAGtg-3′ (SEQ ID NO: 384)3′-CGACGGAGUCGAGGAGUCACGUGUCAC-5′ (SEQ ID NO: 6) HIF-1α-123 Target:5′-GCTGCCTCAGCTCCTCAGTGCACAGTG-3′ (SEQ ID NO: 762)5′-GCCUCAGCUCCUCAGUGCACAGUgc-3′ (SEQ ID NO: 385)3′-GACGGAGUCGAGGAGUCACGUGUCACG-5′ (SEQ ID NO: 7) HIF-1α-124 Target:5′-CTGCCTCAGCTCCTCAGTGCACAGTGC-3′ (SEQ ID NO: 763)5′-CUCAGCUCCUCAGUGCACAGUGCtg-3′ (SEQ ID NO: 386)3′-CGGAGUCGAGGAGUCACGUGUCACGAC-5′ (SEQ ID NO: 8) HIF-1α-126 Target:5′-GCCTCAGCTCCTCAGTGCACAGTGCTG-3′ (SEQ ID NO: 764)5′-GCUCCUCAGUGCACAGUGCUGCCtc-3′ (SEQ ID NO: 387)3′-GUCGAGGAGUCACGUGUCACGACGGAG-5′ (SEQ ID NO: 9) HIF-1α-130 Target:5′-CAGCTCCTCAGTGCACAGTGCTGCCTC-3′ (SEQ ID NO: 765)5′-CUCCUCAGUGCACAGUGCUGCCUcg-3′ (SEQ ID NO: 388)3′-UCGAGGAGUCACGUGUCACGACGGAGC-5′ (SEQ ID NO: 10) HIF-1α-131 Target:5′-AGCTCCTCAGTGCACAGTGCTGCCTCG-3′ (SEQ ID NO: 766)5′-GCUGCCUCGUCUGAGGGGACAGGag-3′ (SEQ ID NO: 389)3′-CACGACGGAGCAGACUCCCCUGUCCUC-5′ (SEQ ID NO: 11) HIF-1α-147 Target:5′-GTGCTGCCTCGTCTGAGGGGACAGGAG-3′ (SEQ ID NO: 767)5′-UUGCCGCCCGCUUCUCUCUAGUCtc-3′ (SEQ ID NO: 390)3′-CUAACGGCGGGCGAAGAGAGAUCAGAG-5′ (SEQ ID NO: 12) HIF-1α-265 Target:5′-GATTGCCGCCCGCTTCTCTCTAGTCTC-3′ (SEQ ID NO: 768)5′-GCCGCCCGCUUCUCUCUAGUCUCac-3′ (SEQ ID NO: 391)3′-AACGGCGGGCGAAGAGAGAUCAGAGUG-5′ (SEQ ID NO: 13) HIF-1α-267 Target:5′-TTGCCGCCCGCTTCTCTCTAGTCTCAC-3′ (SEQ ID NO: 769)5′-CCGCCCGCUUCUCUCUAGUCUCAcg-3′ (SEQ ID NO: 392)3′-ACGGCGGGCGAAGAGAGAUCAGAGUGC-5′ (SEQ ID NO: 14) HIF-1α-268 Target:5′-TGCCGCCCGCTTCTCTCTAGTCTCACG-3′ (SEQ ID NO: 770)5′-GAGGGGUUUCCCGCCUCGCACCCcc-3′ (SEQ ID NO: 393)3′-UGCUCCCCAAAGGGCGGAGCGUGGGGG-5′ (SEQ ID NO: 15) HIF-1α-292 Target:5′-ACGAGGGGTTTCCCGCCTCGCACCCCC-3′ (SEQ ID NO: 771)5′-CUCUGGACUUGCCUUUCCUUCUCtt-3′ (SEQ ID NO: 394)3′-UGGAGACCUGAACGGAAAGGAAGAGAA-5′ (SEQ ID NO: 16) HIF-1α-319 Target:5′-ACCTCTGGACTTGCCTTTCCTTCTCTT-3′ (SEQ ID NO: 772)5′-UGGACUUGCCUUUCCUUCUCUUCtc-3′ (SEQ ID NO: 395)3′-AGACCUGAACGGAAAGGAAGAGAAGAG-5′ (SEQ ID NO: 17) HIF-1α-322 Target:5′-TCTGGACTTGCCTTTCCTTCTCTTCTC-3′ (SEQ ID NO: 773)5′-GACUUGCCUUUCCUUCUCUUCUCcg-3′ (SEQ ID NO: 396)3′-ACCUGAACGGAAAGGAAGAGAAGAGGC-5′ (SEQ ID NO: 18) HIF-1α-324 Target:5′-TGGACTTGCCTTTCCTTCTCTTCTCCG-3′ (SEQ ID NO: 774)5′-UUGCCUUUCCUUCUCUUCUCCGCgt-3′ (SEQ ID NO: 397)3′-UGAACGGAAAGGAAGAGAAGAGGCGCA-5′ (SEQ ID NO: 19) HIF-1α-327 Target:5′-ACTTGCCTTTCCTTCTCTTCTCCGCGT-3′ (SEQ ID NO: 775)5′-GCCUUUCCUUCUCUUCUCCGCGUgt-3′ (SEQ ID NO: 398)3′-AACGGAAAGGAAGAGAAGAGGCGCACA-5′ (SEQ ID NO: 20) HIF-1α-329 Target:5′-TTGCCTTTCCTTCTCTTCTCCGCGTGT-3′ (SEQ ID NO: 776)5′-CCUUUCCUUCUCUUCUCCGCGUGtg-3′ (SEQ ID NO: 399)3′-ACGGAAAGGAAGAGAAGAGGCGCACAC-5′ (SEQ ID NO: 21) HIF-1α-330 Target:5′-TGCCTTTCCTTCTCTTCTCCGCGTGTG-3′ (SEQ ID NO: 777)5′-CUUUCCUUCUCUUCUCCGCGUGUgg-3′ (SEQ ID NO: 400)3′-CGGAAAGGAAGAGAAGAGGCGCACACC-5′ (SEQ ID NO: 22) HIF-1α-331 Target:5′-GCCTTTCCTTCTCTTCTCCGCGTGTGG-3′ (SEQ ID NO: 778)5′-UUCUCCGCGUGUGGAGGGAGCCAgc-3′ (SEQ ID NO: 401)3′-AGAAGAGGCGCACACCUCCCUCGGUCG-5′ (SEQ ID NO: 23) HIF-1α-342 Target:5′-TCTTCTCCGCGTGTGGAGGGAGCCAGC-3′ (SEQ ID NO: 779)5′-CUCCGCGUGUGGAGGGAGCCAGCgc-3′ (SEQ ID NO: 402)3′-AAGAGGCGCACACCUCCCUCGGUCGCG-5′ (SEQ ID NO: 24) HIF-1α-344 Target:5′-TTCTCCGCGTGTGGAGGGAGCCAGCGC-3′ (SEQ ID NO: 780)5′-CCGCGUGUGGAGGGAGCCAGCGCtt-3′ (SEQ ID NO: 403)3′-GAGGCGCACACCUCCCUCGGUCGCGAA-5′ (SEQ ID NO: 25) HIF-1α-346 Target:5′-CTCCGCGTGTGGAGGGAGCCAGCGCTT-3′ (SEQ ID NO: 781)5′-GAGCCAGCGCUUAGGCCGGAGCGag-3′ (SEQ ID NO: 404)3′-CCCUCGGUCGCGAAUCCGGCCUCGCUC-5′ (SEQ ID NO: 26) HIF-1α-359 Target:5′-GGGAGCCAGCGCTTAGGCCGGAGCGAG-3′ (SEQ ID NO: 782)5′-GAAGACAUCGCGGGGACCGAUUCac-3′ (SEQ ID NO: 405)3′-CACUUCUGUAGCGCCCCUGGCUAAGUG-5′ (SEQ ID NO: 27) HIF-1α-403 Target:5′-GTGAAGACATCGCGGGGACCGATTCAC-3′ (SEQ ID NO: 783)5′-AUUCACCAUGGAGGGCGCCGGCGgc-3′ (SEQ ID NO: 406)3′-GCUAAGUGGUACCUCCCGCGGCCGCCG-5′ (SEQ ID NO: 28) HIF-1α-422 Target:5′-CGATTCACCATGGAGGGCGCCGGCGGC-3′ (SEQ ID NO: 784)5′-CCAUGGAGGGCGCCGGCGGCGCGaa-3′ (SEQ ID NO: 407)3′-GUGGUACCUCCCGCGGCCGCCGCGCUU-5′ (SEQ ID NO: 29) HIF-1α-427 Target:5′-CACCATGGAGGGCGCCGGCGGCGCGAA-3′ (SEQ ID NO: 785)5′-AUGGAGGGCGCCGGCGGCGCGAAcg-3′ (SEQ ID NO: 408)3′-GGUACCUCCCGCGGCCGCCGCGCUUGC-5′ (SEQ ID NO: 30) HIF-1α-429 Target:5′-CCATGGAGGGCGCCGGCGGCGCGAACG-3′ (SEQ ID NO: 786)5′-CGAACGACAAGAAAAAGAUAAGUtc-3′ (SEQ ID NO: 409)3′-GCGCUUGCUGUUCUUUUUCUAUUCAAG-5′ (SEQ ID NO: 31) HIF-1α-448 Target:5′-CGCGAACGACAAGAAAAAGATAAGTTC-3′ (SEQ ID NO: 787)5′-CAAGAAAAAGAUAAGUUCUGAACgt-3′ (SEQ ID NO: 410)3′-CUGUUCUUUUUCUAUUCAAGACUUGCA-5′ (SEQ ID NO: 32) HIF-1α-455 Target:5′-GACAAGAAAAAGATAAGTTCTGAACGT-3′ (SEQ ID NO: 788)5′-GUUCUGAACGUCGAAAAGAAAAGtc-3′ (SEQ ID NO: 411)3′-UUCAAGACUUGCAGCUUUUCUUUUCAG-5′ (SEQ ID NO: 33) HIF-1α-469 Target:5′-AAGTTCTGAACGTCGAAAAGAAAAGTC-3′ (SEQ ID NO: 789)5′-UCUGAACGUCGAAAAGAAAAGUCtc-3′ (SEQ ID NO: 412)3′-CAAGACUUGCAGCUUUUCUUUUCAGAG-5′ (SEQ ID NO: 34) HIF-1α-471 Target:5′-GTTCTGAACGTCGAAAAGAAAAGTCTC-3′ (SEQ ID NO: 790)5′-UGAACGUCGAAAAGAAAAGUCUCga-3′ (SEQ ID NO: 413)3′-AGACUUGCAGCUUUUCUUUUCAGAGCU-5′ (SEQ ID NO: 35) HIF-1α-473 Target:5′-TCTGAACGTCGAAAAGAAAAGTCTCGA-3′ (SEQ ID NO: 791)5′-AACGUCGAAAAGAAAAGUCUCGAga-3′ (SEQ ID NO: 414)3′-ACUUGCAGCUUUUCUUUUCAGAGCUCU-5′ (SEQ ID NO: 36) HIF-1α-475 Target:5′-TGAACGTCGAAAAGAAAAGTCTCGAGA-3′ (SEQ ID NO: 792)5′-GAAUCUGAAGUUUUUUAUGAGCUtg-3′ (SEQ ID NO: 415)3′-UUCUUAGACUUCAAAAAAUACUCGAAC-5′ (SEQ ID NO: 37) HIF-1α-525 Target:5′-AAGAATCTGAAGTTTTTTATGAGCTTG-3′ (SEQ ID NO: 793)5′-UCUGAAGUUUUUUAUGAGCUUGCtc-3′ (SEQ ID NO: 416)3′-UUAGACUUCAAAAAAUACUCGAACGAG-5′ (SEQ ID NO: 38) HIF-1α-528 Target:5′-AATCTGAAGTTTTTTATGAGCTTGCTC-3′ (SEQ ID NO: 794)5′-UGAAGUUUUUUAUGAGCUUGCUCat-3′ (SEQ ID NO: 417)3′-AGACUUCAAAAAAUACUCGAACGAGUA-5′ (SEQ ID NO: 39) HIF-1α-530 Target:5′-TCTGAAGTTTTTTATGAGCTTGCTCAT-3′ (SEQ ID NO: 795)5′-AAGUUUUUUAUGAGCUUGCUCAUca-3′ (SEQ ID NO: 418)3′-ACUUCAAAAAAUACUCGAACGAGUAGU-5′ (SEQ ID NO: 40) HIF-1α-532 Target:5′-TGAAGTTTTTTATGAGCTTGCTCATCA-3′ (SEQ ID NO: 796)5′-GUUUUUUAUGAGCUUGCUCAUCAgt-3′ (SEQ ID NO: 419)3′-UUCAAAAAAUACUCGAACGAGUAGUCA-5′ (SEQ ID NO: 41) HIF-1α-534 Target:5′-AAGTTTTTTATGAGCTTGCTCATCAGT-3′ (SEQ ID NO: 797)5′-UUUUUAUGAGCUUGCUCAUCAGUtg-3′ (SEQ ID NO: 420)3′-CAAAAAAUACUCGAACGAGUAGUCAAC-5′ (SEQ ID NO: 42) HIF-1α-536 Target:5′-GTTTTTTATGAGCTTGCTCATCAGTTG-3′ (SEQ ID NO: 798)5′-UUUAUGAGCUUGCUCAUCAGUUGcc-3′ (SEQ ID NO: 421)3′-AAAAAUACUCGAACGAGUAGUCAACGG-5′ (SEQ ID NO: 43) HIF-1α-538 Target:5′-TTTTTATGAGCTTGCTCATCAGTTGCC-3′ (SEQ ID NO: 799)5′-UAUGAGCUUGCUCAUCAGUUGCCac-3′ (SEQ ID NO: 422)3′-AAAUACUCGAACGAGUAGUCAACGGUG-5′ (SEQ ID NO: 44) HIF-1α-540 Target:5′-TTTATGAGCTTGCTCATCAGTTGCCAC-3′ (SEQ ID NO: 800)5′-UGAGCUUGCUCAUCAGUUGCCACtt-3′ (SEQ ID NO: 423)3′-AUACUCGAACGAGUAGUCAACGGUGAA-5′ (SEQ ID NO: 45) HIF-1α-542 Target:5′-TATGAGCTTGCTCATCAGTTGCCACTT-3′ (SEQ ID NO: 801)5′-AGCUUGCUCAUCAGUUGCCACUUcc-3′ (SEQ ID NO: 424)3′-ACUCGAACGAGUAGUCAACGGUGAAGG-5′ (SEQ ID NO: 46) HIF-1α-544 Target:5′-TGAGCTTGCTCATCAGTTGCCACTTCC-3′ (SEQ ID NO: 802)5′-CUUGCUCAUCAGUUGCCACUUCCac-3′ (SEQ ID NO: 425)3′-UCGAACGAGUAGUCAACGGUGAAGGUG-5′ (SEQ ID NO: 47) HIF-1α-546 Target:5′-AGCTTGCTCATCAGTTGCCACTTCCAC-3′ (SEQ ID NO: 803)5′-UGCUCAUCAGUUGCCACUUCCACat-3′ (SEQ ID NO: 426)3′-GAACGAGUAGUCAACGGUGAAGGUGUA-5′ (SEQ ID NO: 48) HIF-1α-548 Target:5′-CTTGCTCATCAGTTGCCACTTCCACAT-3′ (SEQ ID NO: 804)5′-CUCAUCAGUUGCCACUUCCACAUaa-3′ (SEQ ID NO: 427)3′-ACGAGUAGUCAACGGUGAAGGUGUAUU-5′ (SEQ ID NO: 49) HIF-1α-550 Target:5′-TGCTCATCAGTTGCCACTTCCACATAA-3′ (SEQ ID NO: 805)5′-CACUUCCACAUAAUGUGAGUUCGca-3′ (SEQ ID NO: 428)3′-CGGUGAAGGUGUAUUACACUCAAGCGU-5′ (SEQ ID NO: 50) HIF-1α-562 Target:5′-GCCACTTCCACATAATGTGAGTTCGCA-3′ (SEQ ID NO: 806)5′-CUUCUGGAUGCUGGUGAUUUGGAta-3′ (SEQ ID NO: 429)3′-UUGAAGACCUACGACCACUAAACCUAU-5′ (SEQ ID NO: 51) HIF-1α-642 Target:5′-AACTTCTGGATGCTGGTGATTTGGATA-3′ (SEQ ID NO: 807)5′-UCUGGAUGCUGGUGAUUUGGAUAtt-3′ (SEQ ID NO: 430)3′-GAAGACCUACGACCACUAAACCUAUAA-5′ (SEQ ID NO: 52) HIF-1α-644 Target:5′-CTTCTGGATGCTGGTGATTTGGATATT-3′ (SEQ ID NO: 808)5′-CUGGAUGCUGGUGAUUUGGAUAUtg-3′ (SEQ ID NO: 431)3′-AAGACCUACGACCACUAAACCUAUAAC-5′ (SEQ ID NO: 53) HIF-1α-645 Target:5′-TTCTGGATGCTGGTGATTTGGATATTG-3′ (SEQ ID NO: 809)5′-UAUUGAAGAUGACAUGAAAGCACag-3′ (SEQ ID NO: 432)3′-CUAUAACUUCUACUGUACUUUCGUGUC-5′ (SEQ ID NO: 54) HIF-1α-665 Target:5′-GATATTGAAGATGACATGAAAGCACAG-3′ (SEQ ID NO: 810)5′-UGAAUUGCUUUUAUUUGAAAGCCtt-3′ (SEQ ID NO: 433)3′-CUACUUAACGAAAAUAAACUUUCGGAA-5′ (SEQ ID NO: 55) HIF-1α-691 Target:5′-GATGAATTGCTTTTATTTGAAAGCCTT-3′ (SEQ ID NO: 811)5′-GAAAGCCUUGGAUGGUUUUGUUAtg-3′ (SEQ ID NO: 434)3′-AACUUUCGGAACCUACCAAAACAAUAC-5′ (SEQ ID NO: 56) HIF-1α-707 Target:5′-TTGAAAGCCTTGGATGGTTTTGTTATG-3′ (SEQ ID NO: 812)5′-GCCUUGGAUGGUUUUGUUAUGGUtc-3′ (SEQ ID NO: 435)3′-UUCGGAACCUACCAAAACAAUACCAAG-5′ (SEQ ID NO: 57) HIF-1α-711 Target:5′-AAGCCTTGGATGGTTTTGTTATGGTTC-3′ (SEQ ID NO: 813)5′-CUUGGAUGGUUUUGUUAUGGUUCtc-3′ (SEQ ID NO: 436)3′-CGGAACCUACCAAAACAAUACCAAGAG-5′ (SEQ ID NO: 58) HIF-1α-713 Target:5′-GCCTTGGATGGTTTTGTTATGGTTCTC-3′ (SEQ ID NO: 814)5′-UGGAUGGUUUUGUUAUGGUUCUCac-3′ (SEQ ID NO: 437)3′-GAACCUACCAAAACAAUACCAAGAGUG-5′ (SEQ ID NO: 59) HIF-1α-715 Target:5′-CTTGGATGGTTTTGTTATGGTTCTCAC-3′ (SEQ ID NO: 815)5′-GAUGGUUUUGUUAUGGUUCUCACag-3′ (SEQ ID NO: 438)3′-ACCUACCAAAACAAUACCAAGAGUGUC-5′ (SEQ ID NO: 60) HIF-1α-717 Target:5′-TGGATGGTTTTGTTATGGTTCTCACAG-3′ (SEQ ID NO: 816)5′-AUUUACAUUUCUGAUAAUGUGAAca-3′ (SEQ ID NO: 439)3′-ACUAAAUGUAAAGACUAUUACACUUGU-5′ (SEQ ID NO: 61) HIF-1α-756 Target:5′-TGATTTACATTTCTGATAATGTGAACA-3′ (SEQ ID NO: 817)5′-GAUUAACUCAGUUUGAACUAACUgg-3′ (SEQ ID NO: 440)3′-CCCUAAUUGAGUCAAACUUGAUUGACC-5′ (SEQ ID NO: 62) HIF-1α-790 Target:5′-GGGATTAACTCAGTTTGAACTAACTGG-3′ (SEQ ID NO: 818)5′-UAACUCAGUUUGAACUAACUGGAca-3′ (SEQ ID NO: 441)3′-UAAUUGAGUCAAACUUGAUUGACCUGU-5′ (SEQ ID NO: 63) HIF-1α-793 Target:5′-ATTAACTCAGTTTGAACTAACTGGACA-3′ (SEQ ID NO: 819)5′-GUUUGAUUUUACUCAUCCAUGUGac-3′ (SEQ ID NO: 442)3′-CACAAACUAAAAUGAGUAGGUACACUG-5′ (SEQ ID NO: 64) HIF-1α-824 Target:5′-GTGTTTGATTTTACTCATCCATGTGAC-3′ (SEQ ID NO: 820)5′-UUGAUUUUACUCAUCCAUGUGACca-3′ (SEQ ID NO: 443)3′-CAAACUAAAAUGAGUAGGUACACUGGU-5′ (SEQ ID NO: 65) HIF-1α-826 Target:5′-GTTTGATTTTACTCATCCATGTGACCA-3′ (SEQ ID NO: 821)5′-GAUUUUACUCAUCCAUGUGACCAtg-3′ (SEQ ID NO: 444)3′-AACUAAAAUGAGUAGGUACACUGGUAC-5′ (SEQ ID NO: 66) HIF-1α-828 Target:5′-TTGATTTTACTCATCCATGTGACCATG-3′ (SEQ ID NO: 822)5′-UUUUACUCAUCCAUGUGACCAUGag-3′ (SEQ ID NO: 445)3′-CUAAAAUGAGUAGGUACACUGGUACUC-5′ (SEQ ID NO: 67) HIF-1α-830 Target:5′-GATTTTACTCATCCATGTGACCATGAG-3′ (SEQ ID NO: 823)5′-UUACUCAUCCAUGUGACCAUGAGga-3′ (SEQ ID NO: 446)3′-AAAAUGAGUAGGUACACUGGUACUCCU-5′ (SEQ ID NO: 68) HIF-1α-832 Target:5′-TTTTACTCATCCATGTGACCATGAGGA-3′ (SEQ ID NO: 824)5′-ACUCAUCCAUGUGACCAUGAGGAaa-3′ (SEQ ID NO: 447)3′-AAUGAGUAGGUACACUGGUACUCCUUU-5′ (SEQ ID NO: 69) HIF-1α-834 Target:5′-TTACTCATCCATGTGACCATGAGGAAA-3′ (SEQ ID NO: 825)5′-UCAUCCAUGUGACCAUGAGGAAAtg-3′ (SEQ ID NO: 448)3′-UGAGUAGGUACACUGGUACUCCUUUAC-5′ (SEQ ID NO: 70) HIF-1α-836 Target:5′-ACTCATCCATGTGACCATGAGGAAATG-3′ (SEQ ID NO: 826)5′-AUCCAUGUGACCAUGAGGAAAUGag-3′ (SEQ ID NO: 449)3′-AGUAGGUACACUGGUACUCCUUUACUC-5′ (SEQ ID NO: 71) HIF-1α-838 Target:5′-TCATCCATGTGACCATGAGGAAATGAG-3′ (SEQ ID NO: 827)5′-CCAUGUGACCAUGAGGAAAUGAGag-3′ (SEQ ID NO: 450)3′-UAGGUACACUGGUACUCCUUUACUCUC-5′ (SEQ ID NO: 72) HIF-1α-840 Target:5′-ATCCATGTGACCATGAGGAAATGAGAG-3′ (SEQ ID NO: 828)5′-AUGUGACCAUGAGGAAAUGAGAGaa-3′ (SEQ ID NO: 451)3′-GGUACACUGGUACUCCUUUACUCUCUU-5′ (SEQ ID NO: 73) HIF-1α-842 Target:5′-CCATGTGACCATGAGGAAATGAGAGAA-3′ (SEQ ID NO: 829)5′-GUGACCAUGAGGAAAUGAGAGAAat-3′ (SEQ ID NO: 452)3′-UACACUGGUACUCCUUUACUCUCUUUA-5′ (SEQ ID NO: 74) HIF-1α-844 Target:5′-ATGTGACCATGAGGAAATGAGAGAAAT-3′ (SEQ ID NO: 830)5′-GACCAUGAGGAAAUGAGAGAAAUgc-3′ (SEQ ID NO: 453)3′-CACUGGUACUCCUUUACUCUCUUUACG-5′ (SEQ ID NO: 75) HIF-1α-846 Target:5′-GTGACCATGAGGAAATGAGAGAAATGC-3′ (SEQ ID NO: 831)5′-CCAUGAGGAAAUGAGAGAAAUGCtt-3′ (SEQ ID NO: 454)3′-CUGGUACUCCUUUACUCUCUUUACGAA-5′ (SEQ ID NO: 76) HIF-1α-848 Target:5′-GACCATGAGGAAATGAGAGAAATGCTT-3′ (SEQ ID NO: 832)5′-AUGAGGAAAUGAGAGAAAUGCUUac-3′ (SEQ ID NO: 455)3′-GGUACUCCUUUACUCUCUUUACGAAUG-5′ (SEQ ID NO: 77) HIF-1α-850 Target:5′-CCATGAGGAAATGAGAGAAATGCTTAC-3′ (SEQ ID NO: 833)5′-GAGGAAAUGAGAGAAAUGCUUACac-3′ (SEQ ID NO: 456)3′-UACUCCUUUACUCUCUUUACGAAUGUG-5′ (SEQ ID NO: 78) HIF-1α-852 Target:5′-ATGAGGAAATGAGAGAAATGCTTACAC-3′ (SEQ ID NO: 834)5′-CGAAGCUUUUUUCUCAGAAUGAAgt-3′ (SEQ ID NO: 457)3′-UCGCUUCGAAAAAAGAGUCUUACUUCA-5′ (SEQ ID NO: 79) HIF-1α-921 Target:5′-AGCGAAGCTTTTTTCTCAGAATGAAGT-3′ (SEQ ID NO: 835)5′-GCUUUUUUCUCAGAAUGAAGUGUac-3′ (SEQ ID NO: 458)3′-UUCGAAAAAAGAGUCUUACUUCACAUG-5′ (SEQ ID NO: 80) HIF-1α-925 Target:5′-AAGCTTTTTTCTCAGAATGAAGTGTAC-3′ (SEQ ID NO: 836)5′-UUUUUUCUCAGAAUGAAGUGUACcc-3′ (SEQ ID NO: 459)3′-CGAAAAAAGAGUCUUACUUCACAUGGG-5′ (SEQ ID NO: 81) HIF-1α-927 Target:5′-GCTTTTTTCTCAGAATGAAGTGTACCC-3′ (SEQ ID NO: 837)5′-UAUGAUACCAACAGUAACCAACCtc-3′ (SEQ ID NO: 460)3′-AUAUACUAUGGUUGUCAUUGGUUGGAG-5′ (SEQ ID NO: 82) HIF-1α-1029 Target:5′-TATATGATACCAACAGTAACCAACCTC-3′ (SEQ ID NO: 838)5′-UGAUACCAACAGUAACCAACCUCag-3′ (SEQ ID NO: 461)3′-AUACUAUGGUUGUCAUUGGUUGGAGUC-5′ (SEQ ID NO: 83) HIF-1α-1031 Target:5′-TATGATACCAACAGTAACCAACCTCAG-3′ (SEQ ID NO: 839)5′-AUACCAACAGUAACCAACCUCAGtg-3′ (SEQ ID NO: 462)3′-ACUAUGGUUGUCAUUGGUUGGAGUCAC-5′ (SEQ ID NO: 84) HIF-1α-1033 Target:5′-TGATACCAACAGTAACCAACCTCAGTG-3′ (SEQ ID NO: 840)5′-ACCAACAGUAACCAACCUCAGUGtg-3′ (SEQ ID NO: 463)3′-UAUGGUUGUCAUUGGUUGGAGUCACAC-5′ (SEQ ID NO: 85) HIF-1α-1035 Target:5′-ATACCAACAGTAACCAACCTCAGTGTG-3′ (SEQ ID NO: 841)5′-CAACAGUAACCAACCUCAGUGUGgg-3′ (SEQ ID NO: 464)3′-UGGUUGUCAUUGGUUGGAGUCACACCC-5′ (SEQ ID NO: 86) HIF-1α-1037 Target:5′-ACCAACAGTAACCAACCTCAGTGTGGG-3′ (SEQ ID NO: 842)5′-ACAGUAACCAACCUCAGUGUGGGta-3′ (SEQ ID NO: 465)3′-GUUGUCAUUGGUUGGAGUCACACCCAU-5′ (SEQ ID NO: 87) HIF-1α-1039 Target:5′-CAACAGTAACCAACCTCAGTGTGGGTA-3′ (SEQ ID NO: 843)5′-AGUAACCAACCUCAGUGUGGGUAta-3′ (SEQ ID NO: 466)3′-UGUCAUUGGUUGGAGUCACACCCAUAU-5′ (SEQ ID NO: 88) HIF-1α-1041 Target:5′-ACAGTAACCAACCTCAGTGTGGGTATA-3′ (SEQ ID NO: 844)5′-UAACCAACCUCAGUGUGGGUAUAag-3′ (SEQ ID NO: 467)3′-UCAUUGGUUGGAGUCACACCCAUAUUC-5′ (SEQ ID NO: 89) HIF-1α-1043 Target:5′-AGTAACCAACCTCAGTGTGGGTATAAG-3′ (SEQ ID NO: 845)5′-ACCAACCUCAGUGUGGGUAUAAGaa-3′ (SEQ ID NO: 468)3′-AUUGGUUGGAGUCACACCCAUAUUCUU-5′ (SEQ ID NO: 90) HIF-1α-1045 Target:5′-TAACCAACCTCAGTGTGGGTATAAGAA-3′ (SEQ ID NO: 846)5′-CCUAUGACCUGCUUGGUGCUGAUtt-3′ (SEQ ID NO: 469)3′-GUGGAUACUGGACGAACCACGACUAAA-5′ (SEQ ID NO: 91) HIF-1α-1074 Target:5′-CACCTATGACCTGCTTGGTGCTGATTT-3′ (SEQ ID NO: 847)5′-CUAUGACCUGCUUGGUGCUGAUUtg-3′ (SEQ ID NO: 470)3′-UGGAUACUGGACGAACCACGACUAAAC-5′ (SEQ ID NO: 92) HIF-1α-1075 Target:5′-ACCTATGACCTGCTTGGTGCTGATTTG-3′ (SEQ ID NO: 848)5′-AUGACCUGCUUGGUGCUGAUUUGtg-3′ (SEQ ID NO: 471)3′-GAUACUGGACGAACCACGACUAAACAC-5′ (SEQ ID NO: 93) HIF-1α-1077 Target:5′-CTATGACCTGCTTGGTGCTGATTTGTG-3′ (SEQ ID NO: 849)5′-GCUUGGUGCUGAUUUGUGAACCCat-3′ (SEQ ID NO: 472)3′-GACGAACCACGACUAAACACUUGGGUA-5′ (SEQ ID NO: 94) HIF-1α-1084 Target:5′-CTGCTTGGTGCTGATTTGTGAACCCAT-3′ (SEQ ID NO: 850)5′-UUGGUGCUGAUUUGUGAACCCAUtc-3′ (SEQ ID NO: 473)3′-CGAACCACGACUAAACACUUGGGUAAG-5′ (SEQ ID NO: 95) HIF-1α-1086 Target:5′-GCTTGGTGCTGATTTGTGAACCCATTC-3′ (SEQ ID NO: 851)5′-GGUGCUGAUUUGUGAACCCAUUCct-3′ (SEQ ID NO: 474)3′-AACCACGACUAAACACUUGGGUAAGGA-5′ (SEQ ID NO: 96) HIF-1α-1088 Target:5′-TTGGTGCTGATTTGTGAACCCATTCCT-3′ (SEQ ID NO: 852)5′-UGCUGAUUUGUGAACCCAUUCCUca-3′ (SEQ ID NO: 475)3′-CCACGACUAAACACUUGGGUAAGGAGU-5′ (SEQ ID NO: 97) HIF-1α-1090 Target:5′-GGTGCTGATTTGTGAACCCATTCCTCA-3′ (SEQ ID NO: 853)5′-CUGAUUUGUGAACCCAUUCCUCAcc-3′ (SEQ ID NO: 476)3′-ACGACUAAACACUUGGGUAAGGAGUGG-5′ (SEQ ID NO: 98) HIF-1α-1092 Target:5′-TGCTGATTTGTGAACCCATTCCTCACC-3′ (SEQ ID NO: 854)5′-GAUUUGUGAACCCAUUCCUCACCca-3′ (SEQ ID NO: 477)3′-GACUAAACACUUGGGUAAGGAGUGGGU-5′ (SEQ ID NO: 99) HIF-1α-1094 Target:5′-CTGATTTGTGAACCCATTCCTCACCCA-3′ (SEQ ID NO: 855)5′-UUUGUGAACCCAUUCCUCACCCAtc-3′ (SEQ ID NO: 478)3′-CUAAACACUUGGGUAAGGAGUGGGUAG-5′ (SEQ ID NO: 100) HIF-1α-1096 Target:5′-GATTTGTGAACCCATTCCTCACCCATC-3′ (SEQ ID NO: 856)5′-CAAAUAUUGAAAUUCCUUUAGAUag-3′ (SEQ ID NO: 479)3′-UAGUUUAUAACUUUAAGGAAAUCUAUC-5′ (SEQ ID NO: 101) HIF-1α-1120 Target:5′-ATCAAATATTGAAATTCCTTTAGATAG-3′ (SEQ ID NO: 857)5′-AAUAUUGAAAUUCCUUUAGAUAGca-3′ (SEQ ID NO: 480)3′-GUUUAUAACUUUAAGGAAAUCUAUCGU-5′ (SEQ ID NO: 102) HIF-1α-1122 Target:5′-CAAATATTGAAATTCCTTTAGATAGCA-3′ (SEQ ID NO: 858)5′-UAUUGAAAUUCCUUUAGAUAGCAag-3′ (SEQ ID NO: 481)3′-UUAUAACUUUAAGGAAAUCUAUCGUUC-5′ (SEQ ID NO: 103) HIF-1α-1124 Target:5′-AATATTGAAATTCCTTTAGATAGCAAG-3′ (SEQ ID NO: 859)5′-UUGAAAUUCCUUUAGAUAGCAAGac-3′ (SEQ ID NO: 482)3′-AUAACUUUAAGGAAAUCUAUCGUUCUG-5′ (SEQ ID NO: 104) HIF-1α-1126 Target:5′-TATTGAAATTCCTTTAGATAGCAAGAC-3′ (SEQ ID NO: 860)5′-GAAAUUCCUUUAGAUAGCAAGACtt-3′ (SEQ ID NO: 483)3′-AACUUUAAGGAAAUCUAUCGUUCUGAA-5′ (SEQ ID NO: 105) HIF-1α-1128 Target:5′-TTGAAATTCCTTTAGATAGCAAGACTT-3′ (SEQ ID NO: 861)5′-AAUUCCUUUAGAUAGCAAGACUUtc-3′ (SEQ ID NO: 484)3′-CUUUAAGGAAAUCUAUCGUUCUGAAAG-5′ (SEQ ID NO: 106) HIF-1α-1130 Target:5′-GAAATTCCTTTAGATAGCAAGACTTTC-3′ (SEQ ID NO: 862)5′-UUCCUUUAGAUAGCAAGACUUUCct-3′ (SEQ ID NO: 485)3′-UUAAGGAAAUCUAUCGUUCUGAAAGGA-5′ (SEQ ID NO: 107) HIF-1α-1132 Target:5′-AATTCCTTTAGATAGCAAGACTTTCCT-3′ (SEQ ID NO: 863)5′-CAGCCUGGAUAUGAAAUUUUCUUat-3′ (SEQ ID NO: 486)3′-GUGUCGGACCUAUACUUUAAAAGAAUA-5′ (SEQ ID NO: 108) HIF-1α-1166 Target:5′-CACAGCCTGGATATGAAATTTTCTTAT-3′ (SEQ ID NO: 864)5′-AUAUGAAAUUUUCUUAUUGUGAUga-3′ (SEQ ID NO: 487)3′-CCUAUACUUUAAAAGAAUAACACUACU-5′ (SEQ ID NO: 109) HIF-1α-1174 Target:5′-GGATATGAAATTTTCTTATTGTGATGA-3′ (SEQ ID NO: 865)5′-GCCGCUCAAUUUAUGAAUAUUAUca-3′ (SEQ ID NO: 488)3′-UCCGGCGAGUUAAAUACUUAUAAUAGU-5′ (SEQ ID NO: 110) HIF-1α-1243 Target:5′-AGGCCGCTCAATTTATGAATATTATCA-3′ (SEQ ID NO: 866)5′-CGCUCAAUUUAUGAAUAUUAUCAtg-3′ (SEQ ID NO: 489)3′-CGGCGAGUUAAAUACUUAUAAUAGUAC-5′ (SEQ ID NO: 111) HIF-1α-1245 Target:5′-GCCGCTCAATTTATGAATATTATCATG-3′ (SEQ ID NO: 867)5′-CUCAAUUUAUGAAUAUUAUCAUGct-3′ (SEQ ID NO: 490)3′-GCGAGUUAAAUACUUAUAAUAGUACGA-5′ (SEQ ID NO: 112) HIF-1α-1247 Target:5′-CGCTCAATTTATGAATATTATCATGCT-3′ (SEQ ID NO: 868)5′-CAAUUUAUGAAUAUUAUCAUGCUtt-3′ (SEQ ID NO: 491)3′-GAGUUAAAUACUUAUAAUAGUACGAAA-5′ (SEQ ID NO: 113) HIF-1α-1249 Target:5′-CTCAATTTATGAATATTATCATGCTTT-3′ (SEQ ID NO: 869)5′-AUUUAUGAAUAUUAUCAUGCUUUgg-3′ (SEQ ID NO: 492)3′-GUUAAAUACUUAUAAUAGUACGAAACC-5′ (SEQ ID NO: 114) HIF-1α-1251 Target:5′-CAATTTATGAATATTATCATGCTTTGG-3′ (SEQ ID NO: 870)5′-UUAUGAAUAUUAUCAUGCUUUGGac-3′ (SEQ ID NO: 493)3′-UAAAUACUUAUAAUAGUACGAAACCUG-5′ (SEQ ID NO: 115) HIF-1α-1253 Target:5′-ATTTATGAATATTATCATGCTTTGGAC-3′ (SEQ ID NO: 871)5′-AUGAAUAUUAUCAUGCUUUGGACtc-3′ (SEQ ID NO: 494)3′-AAUACUUAUAAUAGUACGAAACCUGAG-5′ (SEQ ID NO: 116) HIF-1α-1255 Target:5′-TTATGAATATTATCATGCTTTGGACTC-3′ (SEQ ID NO: 872)5′-GAAUAUUAUCAUGCUUUGGACUCtg-3′ (SEQ ID NO: 495)3′-UACUUAUAAUAGUACGAAACCUGAGAC-5′ (SEQ ID NO: 117) HIF-1α-1257 Target:5′-ATGAATATTATCATGCTTTGGACTCTG-3′ (SEQ ID NO: 873)5′-UUAUCAUGCUUUGGACUCUGAUCat-3′ (SEQ ID NO: 496)3′-AUAAUAGUACGAAACCUGAGACUAGUA-5′ (SEQ ID NO: 118) HIF-1α-1262 Target:5′-TATTATCATGCTTTGGACTCTGATCAT-3′ (SEQ ID NO: 874)5′-UCAUGCUUUGGACUCUGAUCAUCtg-3′ (SEQ ID NO: 497)3′-AUAGUACGAAACCUGAGACUAGUAGAC-5′ (SEQ ID NO: 119) HIF-1α-1265 Target:5′-TATCATGCTTTGGACTCTGATCATCTG-3′ (SEQ ID NO: 875)5′-UGCUUUGGACUCUGAUCAUCUGAcc-3′ (SEQ ID NO: 498)3′-GUACGAAACCUGAGACUAGUAGACUGG-5′ (SEQ ID NO: 120) HIF-1α-1268 Target:5′-CATGCTTTGGACTCTGATCATCTGACC-3′ (SEQ ID NO: 876)5′-UUUGGACUCUGAUCAUCUGACCAaa-3′ (SEQ ID NO: 499)3′-CGAAACCUGAGACUAGUAGACUGGUUU-5′ (SEQ ID NO: 121) HIF-1α-1271 Target:5′-GCTTTGGACTCTGATCATCTGACCAAA-3′ (SEQ ID NO: 877)5′-UCUGAUCAUCUGACCAAAACUCAtc-3′ (SEQ ID NO: 500)3′-UGAGACUAGUAGACUGGUUUUGAGUAG-5′ (SEQ ID NO: 122) HIF-1α-1278 Target:5′-ACTCTGATCATCTGACCAAAACTCATC-3′ (SEQ ID NO: 878)5′-UGAUCAUCUGACCAAAACUCAUCat-3′ (SEQ ID NO: 501)3′-AGACUAGUAGACUGGUUUUGAGUAGUA-5′ (SEQ ID NO: 123) HIF-1α-1280 Target:5′-TCTGATCATCTGACCAAAACTCATCAT-3′ (SEQ ID NO: 879)5′-AUCAUCUGACCAAAACUCAUCAUga-3′ (SEQ ID NO: 502)3′-ACUAGUAGACUGGUUUUGAGUAGUACU-5′ (SEQ ID NO: 124) HIF-1α-1282 Target:5′-TGATCATCTGACCAAAACTCATCATGA-3′ (SEQ ID NO: 880)5′-AUGAUAUGUUUACUAAAGGACAAgt-3′ (SEQ ID NO: 503)3′-AGUACUAUACAAAUGAUUUCCUGUUCA-5′ (SEQ ID NO: 125) HIF-1α-1303 Target:5′-TCATGATATGTTTACTAAAGGACAAGT-3′ (SEQ ID NO: 881)5′-GAUAUGUUUACUAAAGGACAAGUca-3′ (SEQ ID NO: 504)3′-UACUAUACAAAUGAUUUCCUGUUCAGU-5′ (SEQ ID NO: 126) HIF-1α-1305 Target:5′-ATGATATGTTTACTAAAGGACAAGTCA-3′ (SEQ ID NO: 882)5′-UAUGUUUACUAAAGGACAAGUCAcc-3′ (SEQ ID NO: 505)3′-CUAUACAAAUGAUUUCCUGUUCAGUGG-5′ (SEQ ID NO: 127) HIF-1α-1307 Target:5′-GATATGTTTACTAAAGGACAAGTCACC-3′ (SEQ ID NO: 883)5′-UGUUUACUAAAGGACAAGUCACCac-3′ (SEQ ID NO: 506)3′-AUACAAAUGAUUUCCUGUUCAGUGGUG-5′ (SEQ ID NO: 128) HIF-1α-1309 Target:5′-TATGTTTACTAAAGGACAAGTCACCAC-3′ (SEQ ID NO: 884)5′-UUUACUAAAGGACAAGUCACCACag-3′ (SEQ ID NO: 507)3′-ACAAAUGAUUUCCUGUUCAGUGGUGUC-5′ (SEQ ID NO: 129) HIF-1α-1311 Target:5′-TGTTTACTAAAGGACAAGTCACCACAG-3′ (SEQ ID NO: 885)5′-UACUAAAGGACAAGUCACCACAGga-3′ (SEQ ID NO: 508)3′-AAAUGAUUUCCUGUUCAGUGGUGUCCU-5′ (SEQ ID NO: 130) HIF-1α-1313 Target:5′-TTTACTAAAGGACAAGTCACCACAGGA-3′ (SEQ ID NO: 886)5′-CUAAAGGACAAGUCACCACAGGAca-3′ (SEQ ID NO: 509)3′-AUGAUUUCCUGUUCAGUGGUGUCCUGU-5′ (SEQ ID NO: 131) HIF-1α-1315 Target:5′-TACTAAAGGACAAGTCACCACAGGACA-3′ (SEQ ID NO: 887)5′-AAAGGACAAGUCACCACAGGACAgt-3′ (SEQ ID NO: 510)3′-GAUUUCCUGUUCAGUGGUGUCCUGUCA-5′ (SEQ ID NO: 132) HIF-1α-1317 Target:5′-CTAAAGGACAAGTCACCACAGGACAGT-3′ (SEQ ID NO: 888)5′-AGGACAAGUCACCACAGGACAGUac-3′ (SEQ ID NO: 511)3′-UUUCCUGUUCAGUGGUGUCCUGUCAUG-5′ (SEQ ID NO: 133) HIF-1α-1319 Target:5′-AAAGGACAAGTCACCACAGGACAGTAC-3′ (SEQ ID NO: 889)5′-GACAAGUCACCACAGGACAGUACag-3′ (SEQ ID NO: 512)3′-UCCUGUUCAGUGGUGUCCUGUCAUGUC-5′ (SEQ ID NO: 134) HIF-1α-1321 Target:5′-AGGACAAGTCACCACAGGACAGTACAG-3′ (SEQ ID NO: 890)5′-CAAGUCACCACAGGACAGUACAGga-3′ (SEQ ID NO: 513)3′-CUGUUCAGUGGUGUCCUGUCAUGUCCU-5′ (SEQ ID NO: 135) HIF-1α-1323 Target:5′-GACAAGTCACCACAGGACAGTACAGGA-3′ (SEQ ID NO: 891)5′-AGUCACCACAGGACAGUACAGGAtg-3′ (SEQ ID NO: 514)3′-GUUCAGUGGUGUCCUGUCAUGUCCUAC-5′ (SEQ ID NO: 136) HIF-1α-1325 Target:5′-CAAGTCACCACAGGACAGTACAGGATG-3′ (SEQ ID NO: 892)5′-UCACCACAGGACAGUACAGGAUGct-3′ (SEQ ID NO: 515)3′-UCAGUGGUGUCCUGUCAUGUCCUACGA-5′ (SEQ ID NO: 137) HIF-1α-1327 Target:5′-AGTCACCACAGGACAGTACAGGATGCT-3′ (SEQ ID NO: 893)5′-ACCACAGGACAGUACAGGAUGCUtg-3′ (SEQ ID NO: 516)3′-AGUGGUGUCCUGUCAUGUCCUACGAAC-5′ (SEQ ID NO: 138) HIF-1α-1329 Target:5′-TCACCACAGGACAGTACAGGATGCTTG-3′ (SEQ ID NO: 894)5′-CACAGGACAGUACAGGAUGCUUGcc-3′ (SEQ ID NO: 517)3′-UGGUGUCCUGUCAUGUCCUACGAACGG-5′ (SEQ ID NO: 139) HIF-1α-1331 Target:5′-ACCACAGGACAGTACAGGATGCTTGCC-3′ (SEQ ID NO: 895)5′-CAGGACAGUACAGGAUGCUUGCCaa-3′ (SEQ ID NO: 518)3′-GUGUCCUGUCAUGUCCUACGAACGGUU-5′ (SEQ ID NO: 140) HIF-1α-1333 Target:5′-CACAGGACAGTACAGGATGCTTGCCAA-3′ (SEQ ID NO: 896)5′-GGACAGUACAGGAUGCUUGCCAAaa-3′ (SEQ ID NO: 519)3′-GUCCUGUCAUGUCCUACGAACGGUUUU-5′ (SEQ ID NO: 141) HIF-1α-1335 Target:5′-CAGGACAGTACAGGATGCTTGCCAAAA-3′ (SEQ ID NO: 897)5′-ACAGUACAGGAUGCUUGCCAAAAga-3′ (SEQ ID NO: 520)3′-CCUGUCAUGUCCUACGAACGGUUUUCU-5′ (SEQ ID NO: 142) HIF-1α-1337 Target:5′-GGACAGTACAGGATGCTTGCCAAAAGA-3′ (SEQ ID NO: 898)5′-AGUACAGGAUGCUUGCCAAAAGAgg-3′ (SEQ ID NO: 521)3′-UGUCAUGUCCUACGAACGGUUUUCUCC-5′ (SEQ ID NO: 143) HIF-1α-1339 Target:5′-ACAGTACAGGATGCTTGCCAAAAGAGG-3′ (SEQ ID NO: 899)5′-UACAGGAUGCUUGCCAAAAGAGGtg-3′ (SEQ ID NO: 522)3′-UCAUGUCCUACGAACGGUUUUCUCCAC-5′ (SEQ ID NO: 144) HIF-1α-1341 Target:5′-AGTACAGGATGCTTGCCAAAAGAGGTG-3′ (SEQ ID NO: 900)5′-CAGGAUGCUUGCCAAAAGAGGUGga-3′ (SEQ ID NO: 523)3′-AUGUCCUACGAACGGUUUUCUCCACCU-5′ (SEQ ID NO: 145) HIF-1α-1343 Target:5′-TACAGGATGCTTGCCAAAAGAGGTGGA-3′ (SEQ ID NO: 901)5′-GGAUGCUUGCCAAAAGAGGUGGAta-3′ (SEQ ID NO: 524)3′-GUCCUACGAACGGUUUUCUCCACCUAU-5′ (SEQ ID NO: 146) HIF-1α-1345 Target:5′-CAGGATGCTTGCCAAAAGAGGTGGATA-3′ (SEQ ID NO: 902)5′-AUGCUUGCCAAAAGAGGUGGAUAtg-3′ (SEQ ID NO: 525)3′-CCUACGAACGGUUUUCUCCACCUAUAC-5′ (SEQ ID NO: 147) HIF-1α-1347 Target:5′-GGATGCTTGCCAAAAGAGGTGGATATG-3′ (SEQ ID NO: 903)5′-GCUUGCCAAAAGAGGUGGAUAUGtc-3′ (SEQ ID NO: 526)3′-UACGAACGGUUUUCUCCACCUAUACAG-5′ (SEQ ID NO: 148) HIF-1α-1349 Target:5′-ATGCTTGCCAAAAGAGGTGGATATGTC-3′ (SEQ ID NO: 904)5′-UUGCCAAAAGAGGUGGAUAUGUCtg-3′ (SEQ ID NO: 527)3′-CGAACGGUUUUCUCCACCUAUACAGAC-5′ (SEQ ID NO: 149) HIF-1α-1351 Target:5′-GCTTGCCAAAAGAGGTGGATATGTCTG-3′ (SEQ ID NO: 905)5′-GCCAAAAGAGGUGGAUAUGUCUGgg-3′ (SEQ ID NO: 528)3′-AACGGUUUUCUCCACCUAUACAGACCC-5′ (SEQ ID NO: 150) HIF-1α-1353 Target:5′-TTGCCAAAAGAGGTGGATATGTCTGGG-3′ (SEQ ID NO: 906)5′-CAAAAGAGGUGGAUAUGUCUGGGtt-3′ (SEQ ID NO: 529)3′-CGGUUUUCUCCACCUAUACAGACCCAA-5′ (SEQ ID NO: 151) HIF-1α-1355 Target:5′-GCCAAAAGAGGTGGATATGTCTGGGTT-3′ (SEQ ID NO: 907)5′-AAAGAGGUGGAUAUGUCUGGGUUga-3′ (SEQ ID NO: 530)3′-GUUUUCUCCACCUAUACAGACCCAACU-5′ (SEQ ID NO: 152) HIF-1α-1357 Target:5′-CAAAAGAGGTGGATATGTCTGGGTTGA-3′ (SEQ ID NO: 908)5′-AGAGGUGGAUAUGUCUGGGUUGAaa-3′ (SEQ ID NO: 531)3′-UUUCUCCACCUAUACAGACCCAACUUU-5′ (SEQ ID NO: 153) HIF-1α-1359 Target:5′-AAAGAGGTGGATATGTCTGGGTTGAAA-3′ (SEQ ID NO: 909)5′-AGGUGGAUAUGUCUGGGUUGAAAct-3′ (SEQ ID NO: 532)3′-UCUCCACCUAUACAGACCCAACUUUGA-5′ (SEQ ID NO: 154) HIF-1α-1361 Target:5′-AGAGGTGGATATGTCTGGGTTGAAACT-3′ (SEQ ID NO: 910)5′-GUGGAUAUGUCUGGGUUGAAACUca-3′ (SEQ ID NO: 533)3′-UCCACCUAUACAGACCCAACUUUGAGU-5′ (SEQ ID NO: 155) HIF-1α-1363 Target:5′-AGGTGGATATGTCTGGGTTGAAACTCA-3′ (SEQ ID NO: 911)5′-GGAUAUGUCUGGGUUGAAACUCAag-3′ (SEQ ID NO: 534)3′-CACCUAUACAGACCCAACUUUGAGUUC-5′ (SEQ ID NO: 156) HIF-1α-1365 Target:5′-GTGGATATGTCTGGGTTGAAACTCAAG-3′ (SEQ ID NO: 912)5′-AUAUGUCUGGGUUGAAACUCAAGca-3′ (SEQ ID NO: 535)3′-CCUAUACAGACCCAACUUUGAGUUCGU-5′ (SEQ ID NO: 157) HIF-1α-1367 Target:5′-GGATATGTCTGGGTTGAAACTCAAGCA-3′ (SEQ ID NO: 913)5′-AUGUCUGGGUUGAAACUCAAGCAac-3′ (SEQ ID NO: 536)3′-UAUACAGACCCAACUUUGAGUUCGUUG-5′ (SEQ ID NO: 158) HIF-1α-1369 Target:5′-ATATGTCTGGGTTGAAACTCAAGCAAC-3′ (SEQ ID NO: 914)5′-GUCUGGGUUGAAACUCAAGCAACtg-3′ (SEQ ID NO: 537)3′-UACAGACCCAACUUUGAGUUCGUUGAC-5′ (SEQ ID NO: 159) HIF-1α-1371 Target:5′-ATGTCTGGGTTGAAACTCAAGCAACTG-3′ (SEQ ID NO: 915)5′-CUGGGUUGAAACUCAAGCAACUGtc-3′ (SEQ ID NO: 538)3′-CAGACCCAACUUUGAGUUCGUUGACAG-5′ (SEQ ID NO: 160) HIF-1α-1373 Target:5′-GTCTGGGTTGAAACTCAAGCAACTGTC-3′ (SEQ ID NO: 916)5′-GGGUUGAAACUCAAGCAACUGUCat-3′ (SEQ ID NO: 539)3′-GACCCAACUUUGAGUUCGUUGACAGUA-5′ (SEQ ID NO: 161) HIF-1α-1375 Target:5′-CTGGGTTGAAACTCAAGCAACTGTCAT-3′ (SEQ ID NO: 917)5′-GUUGAAACUCAAGCAACUGUCAUat-3′ (SEQ ID NO: 540)3′-CCCAACUUUGAGUUCGUUGACAGUAUA-5′ (SEQ ID NO: 162) HIF-1α-1377 Target:5′-GGGTTGAAACTCAAGCAACTGTCATAT-3′ (SEQ ID NO: 918)5′-UGAAACUCAAGCAACUGUCAUAUat-3′ (SEQ ID NO: 541)3′-CAACUUUGAGUUCGUUGACAGUAUAUA-5′ (SEQ ID NO: 163) HIF-1α-1379 Target:5′-GTTGAAACTCAAGCAACTGTCATATAT-3′ (SEQ ID NO: 919)5′-AAACUCAAGCAACUGUCAUAUAUaa-3′ (SEQ ID NO: 542)3′-ACUUUGAGUUCGUUGACAGUAUAUAUU-5′ (SEQ ID NO: 164) HIF-1α-1381 Target:5′-TGAAACTCAAGCAACTGTCATATATAA-3′ (SEQ ID NO: 920)5′-ACUCAAGCAACUGUCAUAUAUAAca-3′ (SEQ ID NO: 543)3′-UUUGAGUUCGUUGACAGUAUAUAUUGU-5′ (SEQ ID NO: 165) HIF-1α-1383 Target:5′-AAACTCAAGCAACTGTCATATATAACA-3′ (SEQ ID NO: 921)5′-UCAAGCAACUGUCAUAUAUAACAcc-3′ (SEQ ID NO: 544)3′-UGAGUUCGUUGACAGUAUAUAUUGUGG-5′ (SEQ ID NO: 166) HIF-1α-1385 Target:5′-ACTCAAGCAACTGTCATATATAACACC-3′ (SEQ ID NO: 922)5′-AAGCAACUGUCAUAUAUAACACCaa-3′ (SEQ ID NO: 545)3′-AGUUCGUUGACAGUAUAUAUUGUGGUU-5′ (SEQ ID NO: 167) HIF-1α-1387 Target:5′-TCAAGCAACTGTCATATATAACACCAA-3′ (SEQ ID NO: 923)5′-GUGGUAUUAUUCAGCACGACUUGat-3′ (SEQ ID NO: 546)3′-CUCACCAUAAUAAGUCGUGCUGAACUA-5′ (SEQ ID NO: 168) HIF-1α-1456 Target:5′-GAGTGGTATTATTCAGCACGACTTGAT-3′ (SEQ ID NO: 924)5′-GGUAUUAUUCAGCACGACUUGAUtt-3′ (SEQ ID NO: 547)3′-CACCAUAAUAAGUCGUGCUGAACUAAA-5′ (SEQ ID NO: 169) HIF-1α-1458 Target:5′-GTGGTATTATTCAGCACGACTTGATTT-3′ (SEQ ID NO: 925)5′-UAUUAUUCAGCACGACUUGAUUUtc-3′ (SEQ ID NO: 548)3′-CCAUAAUAAGUCGUGCUGAACUAAAAG-5′ (SEQ ID NO: 170) HIF-1α-1460 Target:5′-GGTATTATTCAGCACGACTTGATTTTC-3′ (SEQ ID NO: 926)5′-UUAUUCAGCACGACUUGAUUUUCtc-3′ (SEQ ID NO: 549)3′-AUAAUAAGUCGUGCUGAACUAAAAGAG-5′ (SEQ ID NO: 171) HIF-1α-1462 Target:5′-TATTATTCAGCACGACTTGATTTTCTC-3′ (SEQ ID NO: 927)5′-AUUCAGCACGACUUGAUUUUCUCcc-3′ (SEQ ID NO: 550)3′-AAUAAGUCGUGCUGAACUAAAAGAGGG-5′ (SEQ ID NO: 172) HIF-1α-1464 Target:5′-TTATTCAGCACGACTTGATTTTCTCCC-3′ (SEQ ID NO: 928)5′-UCAGCACGACUUGAUUUUCUCCCtt-3′ (SEQ ID NO: 551)3′-UAAGUCGUGCUGAACUAAAAGAGGGAA-5′ (SEQ ID NO: 173) HIF-1α-1466 Target:5′-ATTCAGCACGACTTGATTTTCTCCCTT-3′ (SEQ ID NO: 929)5′-AGCACGACUUGAUUUUCUCCCUUca-3′ (SEQ ID NO: 552)3′-AGUCGUGCUGAACUAAAAGAGGGAAGU-5′ (SEQ ID NO: 174) HIF-1α-1468 Target:5′-TCAGCACGACTTGATTTTCTCCCTTCA-3′ (SEQ ID NO: 930)5′-CACGACUUGAUUUUCUCCCUUCAac-3′ (SEQ ID NO: 553)3′-UCGUGCUGAACUAAAAGAGGGAAGUUG-5′ (SEQ ID NO: 175) HIF-1α-1470 Target:5′-AGCACGACTTGATTTTCTCCCTTCAAC-3′ (SEQ ID NO: 931)5′-CGACUUGAUUUUCUCCCUUCAACaa-3′ (SEQ ID NO: 554)3′-GUGCUGAACUAAAAGAGGGAAGUUGUU-5′ (SEQ ID NO: 176) HIF-1α-1472 Target:5′-CACGACTTGATTTTCTCCCTTCAACAA-3′ (SEQ ID NO: 932)5′-ACUUGAUUUUCUCCCUUCAACAAac-3′ (SEQ ID NO: 555)3′-GCUGAACUAAAAGAGGGAAGUUGUUUG-5′ (SEQ ID NO: 177) HIF-1α-1474 Target:5′-CGACTTGATTTTCTCCCTTCAACAAAC-3′ (SEQ ID NO: 933)5′-UUGAUUUUCUCCCUUCAACAAACag-3′ (SEQ ID NO: 556)3′-UGAACUAAAAGAGGGAAGUUGUUUGUC-5′ (SEQ ID NO: 178) HIF-1α-1476 Target:5′-ACTTGATTTTCTCCCTTCAACAAACAG-3′ (SEQ ID NO: 934)5′-GAUUUUCUCCCUUCAACAAACAGaa-3′ (SEQ ID NO: 557)3′-AACUAAAAGAGGGAAGUUGUUUGUCUU-5′ (SEQ ID NO: 179) HIF-1α-1478 Target:5′-TTGATTTTCTCCCTTCAACAAACAGAA-3′ (SEQ ID NO: 935)5′-UUUUCUCCCUUCAACAAACAGAAtg-3′ (SEQ ID NO: 558)3′-CUAAAAGAGGGAAGUUGUUUGUCUUAC-5′ (SEQ ID NO: 180) HIF-1α-1480 Target:5′-GATTTTCTCCCTTCAACAAACAGAATG-3′ (SEQ ID NO: 936)5′-UUCUCCCUUCAACAAACAGAAUGtg-3′ (SEQ ID NO: 559)3′-AAAAGAGGGAAGUUGUUUGUCUUACAC-5′ (SEQ ID NO: 181) HIF-1α-1482 Target:5′-TTTTCTCCCTTCAACAAACAGAATGTG-3′ (SEQ ID NO: 937)5′-UUGAAUCUUCAGAUAUGAAAAUGac-3′ (SEQ ID NO: 560)3′-CCAACUUAGAAGUCUAUACUUUUACUG-5′ (SEQ ID NO: 182) HIF-1α-1519 Target:5′-GGTTGAATCTTCAGATATGAAAATGAC-3′ (SEQ ID NO: 938)5′-UCACCAAAGUUGAAUCAGAAGAUac-3′ (SEQ ID NO: 561)3′-UAAGUGGUUUCAACUUAGUCUUCUAUG-5′ (SEQ ID NO: 183) HIF-1α-1552 Target:5′-ATTCACCAAAGTTGAATCAGAAGATAC-3′ (SEQ ID NO: 939)5′-GAUACAAGUAGCCUCUUUGACAAac-3′ (SEQ ID NO: 562)3′-UUCUAUGUUCAUCGGAGAAACUGUUUG-5′ (SEQ ID NO: 184) HIF-1α-1572 Target:5′-AAGATACAAGTAGCCTCTTTGACAAAC-3′ (SEQ ID NO: 940)5′-CAAUCAUAUCUUUAGAUUUUGGCag-3′ (SEQ ID NO: 563)3′-GUGUUAGUAUAGAAAUCUAAAACCGUC-5′ (SEQ ID NO: 185) HIF-1α-1648 Target:5′-CACAATCATATCTTTAGATTTTGGCAG-3′ (SEQ ID NO: 941)5′-AGUACCAUUAUAUAAUGAUGUAAtg-3′ (SEQ ID NO: 564)3′-CUUCAUGGUAAUAUAUUACUACAUUAC-5′ (SEQ ID NO: 186) HIF-1α-1709 Target:5′-GAAGTACCATTATATAATGATGTAATG-3′ (SEQ ID NO: 942)5′-CAUUAUAUAAUGAUGUAAUGCUCcc-3′ (SEQ ID NO: 565)3′-UGGUAAUAUAUUACUACAUUACGAGGG-5′ (SEQ ID NO: 187) HIF-1α-1714 Target:5′-ACCATTATATAATGATGTAATGCTCCC-3′ (SEQ ID NO: 943)5′-UACCCACCGCUGAAACGCCAAAGcc-3′ (SEQ ID NO: 566)3′-UAAUGGGUGGCGACUUUGCGGUUUCGG-5′ (SEQ ID NO: 188) HIF-1α-1786 Target:5′-ATTACCCACCGCTGAAACGCCAAAGCC-3′ (SEQ ID NO: 944)5′-CAAAGCCACUUCGAAGUAGUGCUga-3′ (SEQ ID NO: 567)3′-CGGUUUCGGUGAAGCUUCAUCACGACU-5′ (SEQ ID NO: 189) HIF-1α-1804 Target:5′-GCCAAAGCCACTTCGAAGTAGTGCTGA-3′ (SEQ ID NO: 945)5′-AAGCCACUUCGAAGUAGUGCUGAcc-3′ (SEQ ID NO: 568)3′-GUUUCGGUGAAGCUUCAUCACGACUGG-5′ (SEQ ID NO: 190) HIF-1α-1806 Target:5′-CAAAGCCACTTCGAAGTAGTGCTGACC-3′ (SEQ ID NO: 946)5′-GCCACUUCGAAGUAGUGCUGACCct-3′ (SEQ ID NO: 569)3′-UUCGGUGAAGCUUCAUCACGACUGGGA-5′ (SEQ ID NO: 191) HIF-1α-1808 Target:5′-AAGCCACTTCGAAGTAGTGCTGACCCT-3′ (SEQ ID NO: 947)5′-CACUUCGAAGUAGUGCUGACCCUgc-3′ (SEQ ID NO: 570)3′-CGGUGAAGCUUCAUCACGACUGGGACG-5′ (SEQ ID NO: 192) HIF-1α-1810 Target:5′-GCCACTTCGAAGTAGTGCTGACCCTGC-3′ (SEQ ID NO: 948)5′-UCGAAGUAGUGCUGACCCUGCACtc-3′ (SEQ ID NO: 571)3′-GAAGCUUCAUCACGACUGGGACGUGAG-5′ (SEQ ID NO: 193) HIF-1α-1814 Target:5′-CTTCGAAGTAGTGCTGACCCTGCACTC-3′ (SEQ ID NO: 949)5′-GAAGUUGCAUUAAAAUUAGAACCaa-3′ (SEQ ID NO: 572)3′-UUCUUCAACGUAAUUUUAAUCUUGGUU-5′ (SEQ ID NO: 194) HIF-1α-1845 Target:5′-AAGAAGTTGCATTAAAATTAGAACCAA-3′ (SEQ ID NO: 950)5′-AUGGAAGCACUAGACAAAGUUCAcc-3′ (SEQ ID NO: 573)3′-GCUACCUUCGUGAUCUGUUUCAAGUGG-5′ (SEQ ID NO: 195) HIF-1α-1936 Target:5′-CGATGGAAGCACTAGACAAAGTTCACC-3′ (SEQ ID NO: 951)5′-GGAAGCACUAGACAAAGUUCACCtg-3′ (SEQ ID NO: 574)3′-UACCUUCGUGAUCUGUUUCAAGUGGAC-5′ (SEQ ID NO: 196) HIF-1α-1938 Target:5′-ATGGAAGCACTAGACAAAGTTCACCTG-3′ (SEQ ID NO: 952)5′-AAGCACUAGACAAAGUUCACCUGag-3′ (SEQ ID NO: 575)3′-CCUUCGUGAUCUGUUUCAAGUGGACUC-5′ (SEQ ID NO: 197) HIF-1α-1940 Target:5′-GGAAGCACTAGACAAAGTTCACCTGAG-3′ (SEQ ID NO: 953)5′-GCACUAGACAAAGUUCACCUGAGcc-3′ (SEQ ID NO: 576)3′-UUCGUGAUCUGUUUCAAGUGGACUCGG-5′ (SEQ ID NO: 198) HIF-1α-1942 Target:5′-AAGCACTAGACAAAGTTCACCTGAGCC-3′ (SEQ ID NO: 954)5′-ACUAGACAAAGUUCACCUGAGCCta-3′ (SEQ ID NO: 577)3′-CGUGAUCUGUUUCAAGUGGACUCGGAU-5′ (SEQ ID NO: 199) HIF-1α-1944 Target:5′-GCACTAGACAAAGTTCACCTGAGCCTA-3′ (SEQ ID NO: 955)5′-UAGACAAAGUUCACCUGAGCCUAat-3′ (SEQ ID NO: 578)3′-UGAUCUGUUUCAAGUGGACUCGGAUUA-5′ (SEQ ID NO: 200) HIF-1α-1946 Target:5′-ACTAGACAAAGTTCACCTGAGCCTAAT-3′ (SEQ ID NO: 956)5′-AGUGAAUAUUGUUUUUAUGUGGAta-3′ (SEQ ID NO: 579)3′-GGUCACUUAUAACAAAAAUACACCUAU-5′ (SEQ ID NO: 201) HIF-1α-1977 Target:5′-CCAGTGAATATTGTTTTTATGTGGATA-3′ (SEQ ID NO: 957)5′-UUGUUUUUAUGUGGAUAGUGAUAtg-3′ (SEQ ID NO: 580)3′-AUAACAAAAAUACACCUAUCACUAUAC-5′ (SEQ ID NO: 202) HIF-1α-1985 Target:5′-TATTGTTTTTATGTGGATAGTGATATG-3′ (SEQ ID NO: 958)5′-GUAGAAAAACUUUUUGCUGAAGAca-3′ (SEQ ID NO: 581)3′-ACCAUCUUUUUGAAAAACGACUUCUGU-5′ (SEQ ID NO: 203) HIF-1α-2034 Target:5′-TGGTAGAAAAACTTTTTGCTGAAGACA-3′ (SEQ ID NO: 959)5′-CUCCCUAUAUCCCAAUGGAUGAUga-3′ (SEQ ID NO: 582)3′-UCGAGGGAUAUAGGGUUACCUACUACU-5′ (SEQ ID NO: 204) HIF-1α-2116 Target:5′-AGCTCCCTATATCCCAATGGATGATGA-3′ (SEQ ID NO: 960)5′-CCCUAUAUCCCAAUGGAUGAUGAct-3′ (SEQ ID NO: 583)3′-GAGGGAUAUAGGGUUACCUACUACUGA-5′ (SEQ ID NO: 205) HIF-1α-2118 Target:5′-CTCCCTATATCCCAATGGATGATGACT-3′ (SEQ ID NO: 961)5′-CUAUAUCCCAAUGGAUGAUGACUtc-3′ (SEQ ID NO: 584)3′-GGGAUAUAGGGUUACCUACUACUGAAG-5′ (SEQ ID NO: 206) HIF-1α-2120 Target:5′-CCCTATATCCCAATGGATGATGACTTC-3′ (SEQ ID NO: 962)5′-AUAUCCCAAUGGAUGAUGACUUCca-3′ (SEQ ID NO: 585)3′-GAUAUAGGGUUACCUACUACUGAAGGU-5′ (SEQ ID NO: 207) HIF-1α-2122 Target:5′-CTATATCCCAATGGATGATGACTTCCA-3′ (SEQ ID NO: 963)5′-AUCAGUUGUCACCAUUAGAAAGCag-3′ (SEQ ID NO: 586)3′-GCUAGUCAACAGUGGUAAUCUUUCGUC-5′ (SEQ ID NO: 208) HIF-1α-2161 Target:5′-CGATCAGTTGTCACCATTAGAAAGCAG-3′ (SEQ ID NO: 964)5′-GUUCCGCAAGCCCUGAAAGCGCAag-3′ (SEQ ID NO: 587)3′-GUCAAGGCGUUCGGGACUUUCGCGUUC-5′ (SEQ ID NO: 209) HIF-1α-2185 Target:5′-CAGTTCCGCAAGCCCTGAAAGCGCAAG-3′ (SEQ ID NO: 965)5′-UCCGCAAGCCCUGAAAGCGCAAGtc-3′ (SEQ ID NO: 588)3′-CAAGGCGUUCGGGACUUUCGCGUUCAG-5′ (SEQ ID NO: 210) HIF-1α-2187 Target:5′-GTTCCGCAAGCCCTGAAAGCGCAAGTC-3′ (SEQ ID NO: 966)5′-CUGAUGAAUUAAAAACAGUGACAaa-3′ (SEQ ID NO: 589)3′-GUGACUACUUAAUUUUUGUCACUGUUU-5′ (SEQ ID NO: 211) HIF-1α-2290 Target:5′-CACTGATGAATTAAAAACAGTGACAAA-3′ (SEQ ID NO: 967)5′-AAGACAUUAAAAUAUUGAUUGCAtc-3′ (SEQ ID NO: 590)3′-CCUUCUGUAAUUUUAUAACUAACGUAG-5′ (SEQ ID NO: 212) HIF-1α-2326 Target:5′-GGAAGACATTAAAATATTGATTGCATC-3′ (SEQ ID NO: 968)5′-GAGUCAUAGAACAGACAGAAAAAtc-3′ (SEQ ID NO: 591)3′-UCCUCAGUAUCUUGUCUGUCUUUUUAG-5′ (SEQ ID NO: 213) HIF-1α-2452 Target:5′-AGGAGTCATAGAACAGACAGAAAAATC-3′ (SEQ ID NO: 969)5′-GAUACUAGCUUUGCAGAAUGCUCag-3′ (SEQ ID NO: 592)3′-UUCUAUGAUCGAAACGUCUUACGAGUC-5′ (SEQ ID NO: 214) HIF-1α-2555 Target:5′-AAGATACTAGCTTTGCAGAATGCTCAG-3′ (SEQ ID NO: 970)5′-CAGAGAAAGCGAAAAAUGGAACAtg-3′ (SEQ ID NO: 593)3′-GAGUCUCUUUCGCUUUUUACCUUGUAC-5′ (SEQ ID NO: 215) HIF-1α-2577 Target:5′-CTCAGAGAAAGCGAAAAATGGAACATG-3′ (SEQ ID NO: 971)5′-AGCGAAAAAUGGAACAUGAUGGUtc-3′ (SEQ ID NO: 594)3′-UUUCGCUUUUUACCUUGUACUACCAAG-5′ (SEQ ID NO: 216) HIF-1α-2584 Target:5′-AAAGCGAAAAATGGAACATGATGGTTC-3′ (SEQ ID NO: 972)5′-CGAAAAAUGGAACAUGAUGGUUCac-3′ (SEQ ID NO: 595)3′-UCGCUUUUUACCUUGUACUACCAAGUG-5′ (SEQ ID NO: 217) HIF-1α-2586 Target:5′-AGCGAAAAATGGAACATGATGGTTCAC-3′ (SEQ ID NO: 973)5′-AGCAGUAGGAAUUGGAACAUUAUta-3′ (SEQ ID NO: 596)3′-GUUCGUCAUCCUUAACCUUGUAAUAAU-5′ (SEQ ID NO: 218) HIF-1α-2618 Target:5′-CAAGCAGTAGGAATTGGAACATTATTA-3′ (SEQ ID NO: 974)5′-AUCUAGUGAACAGAAUGGAAUGGag-3′ (SEQ ID NO: 597)3′-UUUAGAUCACUUGUCUUACCUUACCUC-5′ (SEQ ID NO: 219) HIF-1α-2705 Target:5′-AAATCTAGTGAACAGAATGGAATGGAG-3′ (SEQ ID NO: 975)5′-CAAAAGACAAUUAUUUUAAUACCct-3′ (SEQ ID NO: 598)3′-UCGUUUUCUGUUAAUAAAAUUAUGGGA-5′ (SEQ ID NO: 220) HIF-1α-2730 Target:5′-AGCAAAAGACAATTATTTTAATACCCT-3′ (SEQ ID NO: 976)5′-AGUGGAUUACCACAGCUGACCAGtt-3′ (SEQ ID NO: 599)3′-UUUCACCUAAUGGUGUCGACUGGUCAA-5′ (SEQ ID NO: 221) HIF-1α-2796 Target:5′-AAAGTGGATTACCACAGCTGACCAGTT-3′ (SEQ ID NO: 977)5′-UGGAUUACCACAGCUGACCAGUUat-3′ (SEQ ID NO: 600)3′-UCACCUAAUGGUGUCGACUGGUCAAUA-5′ (SEQ ID NO: 222) HIF-1α-2798 Target:5′-AGTGGATTACCACAGCTGACCAGTTAT-3′ (SEQ ID NO: 978)5′-GAUUACCACAGCUGACCAGUUAUga-3′ (SEQ ID NO: 601)3′-ACCUAAUGGUGUCGACUGGUCAAUACU-5′ (SEQ ID NO: 223) HIF-1α-2800 Target:5′-TGGATTACCACAGCTGACCAGTTATGA-3′ (SEQ ID NO: 979)5′-UUACCACAGCUGACCAGUUAUGAtt-3′ (SEQ ID NO: 602)3′-CUAAUGGUGUCGACUGGUCAAUACUAA-5′ (SEQ ID NO: 224) HIF-1α-2802 Target:5′-GATTACCACAGCTGACCAGTTATGATT-3′ (SEQ ID NO: 980)5′-GAUUGUGAAGUUAAUGCUCCUAUac-3′ (SEQ ID NO: 603)3′-UACUAACACUUCAAUUACGAGGAUAUG-5′ (SEQ ID NO: 225) HIF-1α-2823 Target:5′-ATGATTGTGAAGTTAATGCTCCTATAC-3′ (SEQ ID NO: 981)5′-AUACAAGGCAGCAGAAACCUACUgc-3′ (SEQ ID NO: 604)3′-GAUAUGUUCCGUCGUCUUUGGAUGACG-5′ (SEQ ID NO: 226) HIF-1α-2844 Target:5′-CTATACAAGGCAGCAGAAACCTACTGC-3′ (SEQ ID NO: 982)5′-ACAAGGCAGCAGAAACCUACUGCag-3′ (SEQ ID NO: 605)3′-UAUGUUCCGUCGUCUUUGGAUGACGUC-5′ (SEQ ID NO: 227) HIF-1α-2846 Target:5′-ATACAAGGCAGCAGAAACCTACTGCAG-3′ (SEQ ID NO: 983)5′-AAGGCAGCAGAAACCUACUGCAGgg-3′ (SEQ ID NO: 606)3′-UGUUCCGUCGUCUUUGGAUGACGUCCC-5′ (SEQ ID NO: 228) HIF-1α-2848 Target:5′-ACAAGGCAGCAGAAACCTACTGCAGGG-3′ (SEQ ID NO: 984)5′-GGCAGCAGAAACCUACUGCAGGGtg-3′ (SEQ ID NO: 607)3′-UUCCGUCGUCUUUGGAUGACGUCCCAC-5′ (SEQ ID NO: 229) HIF-1α-2850 Target:5′-AAGGCAGCAGAAACCTACTGCAGGGTG-3′ (SEQ ID NO: 985)5′-CAGCAGAAACCUACUGCAGGGUGaa-3′ (SEQ ID NO: 608)3′-CCGUCGUCUUUGGAUGACGUCCCACUU-5′ (SEQ ID NO: 230) HIF-1α-2852 Target:5′-GGCAGCAGAAACCTACTGCAGGGTGAA-3′ (SEQ ID NO: 986)5′-GCAGAAACCUACUGCAGGGUGAAga-3′ (SEQ ID NO: 609)3′-GUCGUCUUUGGAUGACGUCCCACUUCU-5′ (SEQ ID NO: 231) HIF-1α-2854 Target:5′-CAGCAGAAACCTACTGCAGGGTGAAGA-3′ (SEQ ID NO: 987)5′-AGAAACCUACUGCAGGGUGAAGAat-3′ (SEQ ID NO: 610)3′-CGUCUUUGGAUGACGUCCCACUUCUUA-5′ (SEQ ID NO: 232) HIF-1α-2856 Target:5′-GCAGAAACCTACTGCAGGGTGAAGAAT-3′ (SEQ ID NO: 988)5′-AAACCUACUGCAGGGUGAAGAAUta-3′ (SEQ ID NO: 611)3′-UCUUUGGAUGACGUCCCACUUCUUAAU-5′ (SEQ ID NO: 233) HIF-1α-2858 Target:5′-AGAAACCTACTGCAGGGTGAAGAATTA-3′ (SEQ ID NO: 989)5′-ACCUACUGCAGGGUGAAGAAUUAct-3′ (SEQ ID NO: 612)3′-UUUGGAUGACGUCCCACUUCUUAAUGA-5′ (SEQ ID NO: 234) HIF-1α-2860 Target:5′-AAACCTACTGCAGGGTGAAGAATTACT-3′ (SEQ ID NO: 990)5′-CUACUGCAGGGUGAAGAAUUACUca-3′ (SEQ ID NO: 613)3′-UGGAUGACGUCCCACUUCUUAAUGAGU-5′ (SEQ ID NO: 235) HIF-1α-2862 Target:5′-ACCTACTGCAGGGTGAAGAATTACTCA-3′ (SEQ ID NO: 991)5′-ACUGCAGGGUGAAGAAUUACUCAga-3′ (SEQ ID NO: 614)3′-GAUGACGUCCCACUUCUUAAUGAGUCU-5′ (SEQ ID NO: 236) HIF-1α-2864 Target:5′-CTACTGCAGGGTGAAGAATTACTCAGA-3′ (SEQ ID NO: 992)5′-UGCAGGGUGAAGAAUUACUCAGAgc-3′ (SEQ ID NO: 615)3′-UGACGUCCCACUUCUUAAUGAGUCUCG-5′ (SEQ ID NO: 237) HIF-1α-2866 Target:5′-ACTGCAGGGTGAAGAATTACTCAGAGC-3′ (SEQ ID NO: 993)5′-CAGGGUGAAGAAUUACUCAGAGCtt-3′ (SEQ ID NO: 616)3′-ACGUCCCACUUCUUAAUGAGUCUCGAA-5′ (SEQ ID NO: 238) HIF-1α-2868 Target:5′-TGCAGGGTGAAGAATTACTCAGAGCTT-3′ (SEQ ID NO: 994)5′-GGGUGAAGAAUUACUCAGAGCUUtg-3′ (SEQ ID NO: 617)3′-GUCCCACUUCUUAAUGAGUCUCGAAAC-5′ (SEQ ID NO: 239) HIF-1α-2870 Target:5′-CAGGGTGAAGAATTACTCAGAGCTTTG-3′ (SEQ ID NO: 995)5′-GUGAAGAAUUACUCAGAGCUUUGga-3′ (SEQ ID NO: 618)3′-CCCACUUCUUAAUGAGUCUCGAAACCU-5′ (SEQ ID NO: 240) HIF-1α-2872 Target:5′-GGGTGAAGAATTACTCAGAGCTTTGGA-3′ (SEQ ID NO: 996)5′-GAAGAAUUACUCAGAGCUUUGGAtc-3′ (SEQ ID NO: 619)3′-CACUUCUUAAUGAGUCUCGAAACCUAG-5′ (SEQ ID NO: 241) HIF-1α-2874 Target:5′-GTGAAGAATTACTCAGAGCTTTGGATC-3′ (SEQ ID NO: 997)5′-AGAAUUACUCAGAGCUUUGGAUCaa-3′ (SEQ ID NO: 620)3′-CUUCUUAAUGAGUCUCGAAACCUAGUU-5′ (SEQ ID NO: 242) HIF-1α-2876 Target:5′-GAAGAATTACTCAGAGCTTTGGATCAA-3′ (SEQ ID NO: 998)5′-AAUUACUCAGAGCUUUGGAUCAAgt-3′ (SEQ ID NO: 621)3′-UCUUAAUGAGUCUCGAAACCUAGUUCA-5′ (SEQ ID NO: 243) HIF-1α-2878 Target:5′-AGAATTACTCAGAGCTTTGGATCAAGT-3′ (SEQ ID NO: 999)5′-UUACUCAGAGCUUUGGAUCAAGUta-3′ (SEQ ID NO: 622)3′-UUAAUGAGUCUCGAAACCUAGUUCAAU-5′ (SEQ ID NO: 244) HIF-1α-2880 Target:5′-AATTACTCAGAGCTTTGGATCAAGTTA-3′ (SEQ ID NO: 1000)5′-ACUCAGAGCUUUGGAUCAAGUUAac-3′ (SEQ ID NO: 623)3′-AAUGAGUCUCGAAACCUAGUUCAAUUG-5′ (SEQ ID NO: 245) HIF-1α-2882 Target:5′-TTACTCAGAGCTTTGGATCAAGTTAAC-3′ (SEQ ID NO: 1001)5′-UCAGAGCUUUGGAUCAAGUUAACtg-3′ (SEQ ID NO: 624)3′-UGAGUCUCGAAACCUAGUUCAAUUGAC-5′ (SEQ ID NO: 246) HIF-1α-2884 Target:5′-ACTCAGAGCTTTGGATCAAGTTAACTG-3′ (SEQ ID NO: 1002)5′-AGAGCUUUGGAUCAAGUUAACUGag-3′ (SEQ ID NO: 625)3′-AGUCUCGAAACCUAGUUCAAUUGACUC-5′ (SEQ ID NO: 247) HIF-1α-2886 Target:5′-TCAGAGCTTTGGATCAAGTTAACTGAG-3′ (SEQ ID NO: 1003)5′-AGCUUUGGAUCAAGUUAACUGAGct-3′ (SEQ ID NO: 626)3′-UCUCGAAACCUAGUUCAAUUGACUCGA-5′ (SEQ ID NO: 248) HIF-1α-2888 Target:5′-AGAGCTTTGGATCAAGTTAACTGAGCT-3′ (SEQ ID NO: 1004)5′-CUUUGGAUCAAGUUAACUGAGCUtt-3′ (SEQ ID NO: 627)3′-UCGAAACCUAGUUCAAUUGACUCGAAA-5′ (SEQ ID NO: 249) HIF-1α-2890 Target:5′-AGCTTTGGATCAAGTTAACTGAGCTTT-3′ (SEQ ID NO: 1005)5′-UUGGAUCAAGUUAACUGAGCUUUtt-3′ (SEQ ID NO: 628)3′-GAAACCUAGUUCAAUUGACUCGAAAAA-5′ (SEQ ID NO: 250) HIF-1α-2892 Target:5′-CTTTGGATCAAGTTAACTGAGCTTTTT-3′ (SEQ ID NO: 1006)5′-GAUCAAGUUAACUGAGCUUUUUCtt-3′ (SEQ ID NO: 629)3′-ACCUAGUUCAAUUGACUCGAAAAAGAA-5′ (SEQ ID NO: 251) HIF-1α-2895 Target:5′-TGGATCAAGTTAACTGAGCTTTTTCTT-3′ (SEQ ID NO: 1007)5′-CUGAGCUUUUUCUUAAUUUCAUUcc-3′ (SEQ ID NO: 630)3′-UUGACUCGAAAAAGAAUUAAAGUAAGG-5′ (SEQ ID NO: 252) HIF-1α-2906 Target:5′-AACTGAGCTTTTTCTTAATTTCATTCC-3′ (SEQ ID NO: 1008)5′-GCUUUUUCUUAAUUUCAUUCCUUtt-3′ (SEQ ID NO: 631)3′-CUCGAAAAAGAAUUAAAGUAAGGAAAA-5′ (SEQ ID NO: 253) HIF-1α-2910 Target:5′-GAGCTTTTTCTTAATTTCATTCCTTTT-3′ (SEQ ID NO: 1009)5′-UAAUUUCAUUCCUUUUUUUGGACac-3′ (SEQ ID NO: 632)3′-GAAUUAAAGUAAGGAAAAAAACCUGUG-5′ (SEQ ID NO: 254) HIF-1α-2919 Target:5′-CTTAATTTCATTCCTTTTTTTGGACAC-3′ (SEQ ID NO: 1010)5′-CAUUCCUUUUUUUGGACACUGGUgg-3′ (SEQ ID NO: 633)3′-AAGUAAGGAAAAAAACCUGUGACCACC-5′ (SEQ ID NO: 255) HIF-1α-2925 Target:5′-TTCATTCCTTTTTTTGGACACTGGTGG-3′ (SEQ ID NO: 1011)5′-UUUUUGGACACUGGUGGCUCAUUac-3′ (SEQ ID NO: 634)3′-AAAAAAACCUGUGACCACCGAGUAAUG-5′ (SEQ ID NO: 256) HIF-1α-2933 Target:5′-TTTTTTTGGACACTGGTGGCTCATTAC-3′ (SEQ ID NO: 1012)5′-UUUGGACACUGGUGGCUCAUUACct-3′ (SEQ ID NO: 635)3′-AAAAACCUGUGACCACCGAGUAAUGGA-5′ (SEQ ID NO: 257) HIF-1α-2935 Target:5′-TTTTTGGACACTGGTGGCTCATTACCT-3′ (SEQ ID NO: 1013)5′-GCAGUCUAUUUAUAUUUUCUACAtc-3′ (SEQ ID NO: 636)3′-UUCGUCAGAUAAAUAUAAAAGAUGUAG-5′ (SEQ ID NO: 258) HIF-1α-2963 Target:5′-AAGCAGTCTATTTATATTTTCTACATC-3′ (SEQ ID NO: 1014)5′-AGUCUAUUUAUAUUUUCUACAUCta-3′ (SEQ ID NO: 637)3′-CGUCAGAUAAAUAUAAAAGAUGUAGAU-5′ (SEQ ID NO: 259) HIF-1α-2965 Target:5′-GCAGTCTATTTATATTTTCTACATCTA-3′ (SEQ ID NO: 1015)5′-AUUUAUAUUUUCUACAUCUAAUUtt-3′ (SEQ ID NO: 638)3′-GAUAAAUAUAAAAGAUGUAGAUUAAAA-5′ (SEQ ID NO: 260) HIF-1α-2970 Target:5′-CTATTTATATTTTCTACATCTAATTTT-3′ (SEQ ID NO: 1016)5′-UCUAAUUUUAGAAGCCUGGCUACaa-3′ (SEQ ID NO: 639)3′-GUAGAUUAAAAUCUUCGGACCGAUGUU-5′ (SEQ ID NO: 261) HIF-1α-2986 Target:5′-CATCTAATTTTAGAAGCCTGGCTACAA-3′ (SEQ ID NO: 1017)5′-UAAUUUUAGAAGCCUGGCUACAAta-3′ (SEQ ID NO: 640)3′-AGAUUAAAAUCUUCGGACCGAUGUUAU-5′ (SEQ ID NO: 262) HIF-1α-2988 Target:5′-TCTAATTTTAGAAGCCTGGCTACAATA-3′ (SEQ ID NO: 1018)5′-AUUUUAGAAGCCUGGCUACAAUAct-3′ (SEQ ID NO: 641)3′-AUUAAAAUCUUCGGACCGAUGUUAUGA-5′ (SEQ ID NO: 263) HIF-1α-2990 Target:5′-TAATTTTAGAAGCCTGGCTACAATACT-3′ (SEQ ID NO: 1019)5′-UUUAGAAGCCUGGCUACAAUACUgc-3′ (SEQ ID NO: 642)3′-UAAAAUCUUCGGACCGAUGUUAUGACG-5′ (SEQ ID NO: 264) HIF-1α-2992 Target:5′-ATTTTAGAAGCCTGGCTACAATACTGC-3′ (SEQ ID NO: 1020)5′-UAGAAGCCUGGCUACAAUACUGCac-3′ (SEQ ID NO: 643)3′-AAAUCUUCGGACCGAUGUUAUGACGUG-5′ (SEQ ID NO: 265) HIF-1α-2994 Target:5′-TTTAGAAGCCTGGCTACAATACTGCAC-3′ (SEQ ID NO: 1021)5′-GAAGCCUGGCUACAAUACUGCACaa-3′ (SEQ ID NO: 644)3′-AUCUUCGGACCGAUGUUAUGACGUGUU-5′ (SEQ ID NO: 266) HIF-1α-2996 Target:5′-TAGAAGCCTGGCTACAATACTGCACAA-3′ (SEQ ID NO: 1022)5′-AGCCUGGCUACAAUACUGCACAAac-3′ (SEQ ID NO: 645)3′-CUUCGGACCGAUGUUAUGACGUGUUUG-5′ (SEQ ID NO: 267) HIF-1α-2998 Target:5′-GAAGCCTGGCTACAATACTGCACAAAC-3′ (SEQ ID NO: 1023)5′-CCUGGCUACAAUACUGCACAAACtt-3′ (SEQ ID NO: 646)3′-UCGGACCGAUGUUAUGACGUGUUUGAA-5′ (SEQ ID NO: 268) HIF-1α-3000 Target:5′-AGCCTGGCTACAATACTGCACAAACTT-3′ (SEQ ID NO: 1024)5′-UGGCUACAAUACUGCACAAACUUgg-3′ (SEQ ID NO: 647)3′-GGACCGAUGUUAUGACGUGUUUGAACC-5′ (SEQ ID NO: 269) HIF-1α-3002 Target:5′-CCTGGCTACAATACTGCACAAACTTGG-3′ (SEQ ID NO: 1025)5′-GCUACAAUACUGCACAAACUUGGtt-3′ (SEQ ID NO: 648)3′-ACCGAUGUUAUGACGUGUUUGAACCAA-5′ (SEQ ID NO: 270) HIF-1α-3004 Target:5′-TGGCTACAATACTGCACAAACTTGGTT-3′ (SEQ ID NO: 1026)5′-UAAUUUACAUUAAUGCUCUUUUUta-3′ (SEQ ID NO: 649)3′-GAAUUAAAUGUAAUUACGAGAAAAAAU-5′ (SEQ ID NO: 271) HIF-1α-3055 Target:5′-CTTAATTTACATTAATGCTCTTTTTTA-3′ (SEQ ID NO: 1027)5′-UAAUGCUCUUUUUUAGUAUGUUCtt-3′ (SEQ ID NO: 650)3′-UAAUUACGAGAAAAAAUCAUACAAGAA-5′ (SEQ ID NO: 272) HIF-1α-3065 Target:5′-ATTAATGCTCTTTTTTAGTATGTTCTT-3′ (SEQ ID NO: 1028)5′-AUGCUCUUUUUUAGUAUGUUCUUta-3′ (SEQ ID NO: 651)3′-AUUACGAGAAAAAAUCAUACAAGAAAU-5′ (SEQ ID NO: 273) HIF-1α-3067 Target:5′-TAATGCTCTTTTTTAGTATGTTCTTTA-3′ (SEQ ID NO: 1029)5′-UGCUCUUUUUUAGUAUGUUCUUUaa-3′ (SEQ ID NO: 652)3′-UUACGAGAAAAAAUCAUACAAGAAAUU-5′ (SEQ ID NO: 274) HIF-1α-3068 Target:5′-AATGCTCTTTTTTAGTATGTTCTTTAA-3′ (SEQ ID NO: 1030)5′-UUAGUAUGUUCUUUAAUGCUGGAtc-3′ (SEQ ID NO: 653)3′-AAAAUCAUACAAGAAAUUACGACCUAG-5′ (SEQ ID NO: 275) HIF-1α-3077 Target:5′-TTTTAGTATGTTCTTTAATGCTGGATC-3′ (SEQ ID NO: 1031)5′-UAUGUUCUUUAAUGCUGGAUCACag-3′ (SEQ ID NO: 654)3′-UCAUACAAGAAAUUACGACCUAGUGUC-5′ (SEQ ID NO: 276) HIF-1α-3081 Target:5′-AGTATGTTCTTTAATGCTGGATCACAG-3′ (SEQ ID NO: 1032)5′-UUUAAUGCUGGAUCACAGACAGCtc-3′ (SEQ ID NO: 655)3′-AGAAAUUACGACCUAGUGUCUGUCGAG-5′ (SEQ ID NO: 277) HIF-1α-3088 Target:5′-TCTTTAATGCTGGATCACAGACAGCTC-3′ (SEQ ID NO: 1033)5′-UGCUGGAUCACAGACAGCUCAUUtt-3′ (SEQ ID NO: 656)3′-UUACGACCUAGUGUCUGUCGAGUAAAA-5′ (SEQ ID NO: 278) HIF-1α-3093 Target:5′-AATGCTGGATCACAGACAGCTCATTTT-3′ (SEQ ID NO: 1034)5′-CUCAUUUUCUCAGUUUUUUGGUAtt-3′ (SEQ ID NO: 657)3′-UCGAGUAAAAGAGUCAAAAAACCAUAA-5′ (SEQ ID NO: 279) HIF-1α-3110 Target:5′-AGCTCATTTTCTCAGTTTTTTGGTATT-3′ (SEQ ID NO: 1035)5′-AAAAUGCACCUUUUUAUUUAUUUat-3′ (SEQ ID NO: 658)3′-UUUUUUACGUGGAAAAAUAAAUAAAUA-5′ (SEQ ID NO: 280) HIF-1α-3167 Target:5′-AAAAAATGCACCTTTTTATTTATTTAT-3′ (SEQ ID NO: 1036)5′-AAUGCACCUUUUUAUUUAUUUAUtt-3′ (SEQ ID NO: 659)3′-UUUUACGUGGAAAAAUAAAUAAAUAAA-5′ (SEQ ID NO: 281) HIF-1α-3169 Target:5′-AAAATGCACCTTTTTATTTATTTATTT-3′ (SEQ ID NO: 1037)5′-UGCACCUUUUUAUUUAUUUAUUUtt-3′ (SEQ ID NO: 660)3′-UUACGUGGAAAAAUAAAUAAAUAAAAA-5′ (SEQ ID NO: 282) HIF-1α-3171 Target:5′-AATGCACCTTTTTATTTATTTATTTTT-3′ (SEQ ID NO: 1038)5′-CACCUUUUUAUUUAUUUAUUUUUgg-3′ (SEQ ID NO: 661)3′-ACGUGGAAAAAUAAAUAAAUAAAAACC-5′ (SEQ ID NO: 283) HIF-1α-3173 Target:5′-TGCACCTTTTTATTTATTTATTTTTGG-3′ (SEQ ID NO: 1039)5′-CCUUUUUAUUUAUUUAUUUUUGGct-3′ (SEQ ID NO: 662)3′-GUGGAAAAAUAAAUAAAUAAAAACCGA-5′ (SEQ ID NO: 284) HIF-1α-3175 Target:5′-CACCTTTTTATTTATTTATTTTTGGCT-3′ (SEQ ID NO: 1040)5′-UUUUUAUUUAUUUAUUUUUGGCUag-3′ (SEQ ID NO: 663)3′-GGAAAAAUAAAUAAAUAAAAACCGAUC-5′ (SEQ ID NO: 285) HIF-1α-3177 Target:5′-CCTTTTTATTTATTTATTTTTGGCTAG-3′ (SEQ ID NO: 1041)5′-UUUAUUUAUUUAUUUUUGGCUAGgg-3′ (SEQ ID NO: 664)3′-AAAAAUAAAUAAAUAAAAACCGAUCCC-5′ (SEQ ID NO: 286) HIF-1α-3179 Target:5′-TTTTTATTTATTTATTTTTGGCTAGGG-3′ (SEQ ID NO: 1042)5′-UUUUCGAAUUAUUUUUAAGAAGAtg-3′ (SEQ ID NO: 665)3′-GAAAAAGCUUAAUAAAAAUUCUUCUAC-5′ (SEQ ID NO: 287) HIF-1α-3215 Target:5′-CTTTTTCGAATTATTTTTAAGAAGATG-3′ (SEQ ID NO: 1043)5′-CAAUAUAAUUUUUGUAAGAAGGCag-3′ (SEQ ID NO: 666)3′-CGGUUAUAUUAAAAACAUUCUUCCGUC-5′ (SEQ ID NO: 288) HIF-1α-3241 Target:5′-GCCAATATAATTTTTGTAAGAAGGCAG-3′ (SEQ ID NO: 1044)5′-CAUCAUGAUCAUAGGCAGUUGAAaa-3′ (SEQ ID NO: 667)3′-AAGUAGUACUAGUAUCCGUCAACUUUU-5′ (SEQ ID NO: 289) HIF-1α-3274 Target:5′-TTCATCATGATCATAGGCAGTTGAAAA-3′ (SEQ ID NO: 1045)5′-UCAUGAUCAUAGGCAGUUGAAAAat-3′ (SEQ ID NO: 668)3′-GUAGUACUAGUAUCCGUCAACUUUUUA-5′ (SEQ ID NO: 290) HIF-1α-3276 Target:5′-CATCATGATCATAGGCAGTTGAAAAAT-3′ (SEQ ID NO: 1046)5′-AUGAUCAUAGGCAGUUGAAAAAUtt-3′ (SEQ ID NO: 669)3′-AGUACUAGUAUCCGUCAACUUUUUAAA-5′ (SEQ ID NO: 291) HIF-1α-3278 Target:5′-TCATGATCATAGGCAGTTGAAAAATTT-3′ (SEQ ID NO: 1047)5′-GAUCAUAGGCAGUUGAAAAAUUUtt-3′ (SEQ ID NO: 670)3′-UACUAGUAUCCGUCAACUUUUUAAAAA-5′ (SEQ ID NO: 292) HIF-1α-3280 Target:5′-ATGATCATAGGCAGTTGAAAAATTTTT-3′ (SEQ ID NO: 1048)5′-UUGAAAAAUUUUUACACCUUUUUtt-3′ (SEQ ID NO: 671)3′-UCAACUUUUUAAAAAUGUGGAAAAAAA-5′ (SEQ ID NO: 293) HIF-1α-3292 Target:5′-AGTTGAAAAATTTTTACACCTTTTTTT-3′ (SEQ ID NO: 1049)5′-UUUUUUUUCACAUUUUACAUAAAta-3′ (SEQ ID NO: 672)3′-GGAAAAAAAAGUGUAAAAUGUAUUUAU-5′ (SEQ ID NO: 294) HIF-1α-3310 Target:5′-CCTTTTTTTTCACATTTTACATAAATA-3′ (SEQ ID NO: 1050)5′-GGUAGCCACAAUUGCACAAUAUAtt-3′ (SEQ ID NO: 673)3′-CACCAUCGGUGUUAACGUGUUAUAUAA-5′ (SEQ ID NO: 295) HIF-1α-3358 Target:5′-GTGGTAGCCACAATTGCACAATATATT-3′ (SEQ ID NO: 1051)5′-UAGCCACAAUUGCACAAUAUAUUtt-3′ (SEQ ID NO: 674)3′-CCAUCGGUGUUAACGUGUUAUAUAAAA-5′ (SEQ ID NO: 296) HIF-1α-3360 Target:5′-GGTAGCCACAATTGCACAATATATTTT-3′ (SEQ ID NO: 1052)5′-GCCACAAUUGCACAAUAUAUUUUct-3′ (SEQ ID NO: 675)3′-AUCGGUGUUAACGUGUUAUAUAAAAGA-5′ (SEQ ID NO: 297) HIF-1α-3362 Target:5′-TAGCCACAATTGCACAATATATTTTCT-3′ (SEQ ID NO: 1053)5′-CACAAUUGCACAAUAUAUUUUCUta-3′ (SEQ ID NO: 676)3′-CGGUGUUAACGUGUUAUAUAAAAGAAU-5′ (SEQ ID NO: 298) HIF-1α-3364 Target:5′-GCCACAATTGCACAATATATTTTCTTA-3′ (SEQ ID NO: 1054)5′-CAAUUGCACAAUAUAUUUUCUUAaa-3′ (SEQ ID NO: 677)3′-GUGUUAACGUGUUAUAUAAAAGAAUUU-5′ (SEQ ID NO: 299) HIF-1α-3366 Target:5′-CACAATTGCACAATATATTTTCTTAAA-3′ (SEQ ID NO: 1055)5′-AUUGCACAAUAUAUUUUCUUAAAaa-3′ (SEQ ID NO: 678)3′-GUUAACGUGUUAUAUAAAAGAAUUUUU-5′ (SEQ ID NO: 300) HIF-1α-3368 Target:5′-CAATTGCACAATATATTTTCTTAAAAA-3′ (SEQ ID NO: 1056)5′-CAAUAUAUUUUCUUAAAAAAUACca-3′ (SEQ ID NO: 679)3′-GUGUUAUAUAAAAGAAUUUUUUAUGGU-5′ (SEQ ID NO: 301) HIF-1α-3374 Target:5′-CACAATATATTTTCTTAAAAAATACCA-3′ (SEQ ID NO: 1057)5′-GUUUAUAAAACUAGUUUUUAAGAag-3′ (SEQ ID NO: 680)3′-CGCAAAUAUUUUGAUCAAAAAUUCUUC-5′ (SEQ ID NO: 302) HIF-1α-3425 Target:5′-GCGTTTATAAAACTAGTTTTTAAGAAG-3′ (SEQ ID NO: 1058)5′-UUUAUAAAACUAGUUUUUAAGAAga-3′ (SEQ ID NO: 681)3′-GCAAAUAUUUUGAUCAAAAAUUCUUCU-5′ (SEQ ID NO: 303) HIF-1α-3426 Target:5′-CGTTTATAAAACTAGTTTTTAAGAAGA-3′ (SEQ ID NO: 1059)5′-UAUAAAACUAGUUUUUAAGAAGAaa-3′ (SEQ ID NO: 682)3′-AAAUAUUUUGAUCAAAAAUUCUUCUUU-5′ (SEQ ID NO: 304) HIF-1α-3428 Target:5′-TTTATAAAACTAGTTTTTAAGAAGAAA-3′ (SEQ ID NO: 1060)5′-UAAAACUAGUUUUUAAGAAGAAAtt-3′ (SEQ ID NO: 683)3′-AUAUUUUGAUCAAAAAUUCUUCUUUAA-5′ (SEQ ID NO: 305) HIF-1α-3430 Target:5′-TATAAAACTAGTTTTTAAGAAGAAATT-3′ (SEQ ID NO: 1061)5′-UUAAGAAGAAAUUUUUUUUGGCCta-3′ (SEQ ID NO: 684)3′-AAAAUUCUUCUUUAAAAAAAACCGGAU-5′ (SEQ ID NO: 306) HIF-1α-3442 Target:5′-TTTTAAGAAGAAATTTTTTTTGGCCTA-3′ (SEQ ID NO: 1062)5′-AGAAAUUUUUUUUGGCCUAUGAAat-3′ (SEQ ID NO: 685)3′-CUUCUUUAAAAAAAACCGGAUACUUUA-5′ (SEQ ID NO: 307) HIF-1α-3448 Target:5′-GAAGAAATTTTTTTTGGCCTATGAAAT-3′ (SEQ ID NO: 1063)5′-AAAUUUUUUUUGGCCUAUGAAAUtg-3′ (SEQ ID NO: 686)3′-UCUUUAAAAAAAACCGGAUACUUUAAC-5′ (SEQ ID NO: 308) HIF-1α-3450 Target:5′-AGAAATTTTTTTTGGCCTATGAAATTG-3′ (SEQ ID NO: 1064)5′-UAUGAAAUUGUUAAACCUGGAACat-3′ (SEQ ID NO: 687)3′-GGAUACUUUAACAAUUUGGACCUUGUA-5′ (SEQ ID NO: 309) HIF-1α-3465 Target:5′-CCTATGAAATTGTTAAACCTGGAACAT-3′ (SEQ ID NO: 1065)5′-AUUGUUAAUCAUAUAAUAAUGAUtc-3′ (SEQ ID NO: 688)3′-UGUAACAAUUAGUAUAUUAUUACUAAG-5′ (SEQ ID NO: 310) HIF-1α-3493 Target:5′-ACATTGTTAATCATATAATAATGATTC-3′ (SEQ ID NO: 1066)5′-AUGGUUUAUUAUUUAAAUGGGUAaa-3′ (SEQ ID NO: 689)3′-CAUACCAAAUAAUAAAUUUACCCAUUU-5′ (SEQ ID NO: 311) HIF-1α-3529 Target:5′-GTATGGTTTATTATTTAAATGGGTAAA-3′ (SEQ ID NO: 1067)5′-UGGGUAAAGCCAUUUACAUAAUAta-3′ (SEQ ID NO: 690)3′-UUACCCAUUUCGGUAAAUGUAUUAUAU-5′ (SEQ ID NO: 312) HIF-1α-3546 Target:5′-AATGGGTAAAGCCATTTACATAATATA-3′ (SEQ ID NO: 1068)5′-AUUUACAUAAUAUAGAAAGAUAUgc-3′ (SEQ ID NO: 691)3′-GGUAAAUGUAUUAUAUCUUUCUAUACG-5′ (SEQ ID NO: 313) HIF-1α-3557 Target:5′-CCATTTACATAATATAGAAAGATATGC-3′ (SEQ ID NO: 1069)5′-AAGGUAUGUGGCAUUUAUUUGGAta-3′ (SEQ ID NO: 692)3′-UCUUCCAUACACCGUAAAUAAACCUAU-5′ (SEQ ID NO: 314) HIF-1α-3592 Target:5′-AGAAGGTATGTGGCATTTATTTGGATA-3′ (SEQ ID NO: 1070)5′-GGUAUGUGGCAUUUAUUUGGAUAaa-3′ (SEQ ID NO: 693)3′-UUCCAUACACCGUAAAUAAACCUAUUU-5′ (SEQ ID NO: 315) HIF-1α-3594 Target:5′-AAGGTATGTGGCATTTATTTGGATAAA-3′ (SEQ ID NO: 1071)5′-UAUGUGGCAUUUAUUUGGAUAAAat-3′ (SEQ ID NO: 694)3′-CCAUACACCGUAAAUAAACCUAUUUUA-5′ (SEQ ID NO: 316) HIF-1α-3596 Target:5′-GGTATGTGGCATTTATTTGGATAAAAT-3′ (SEQ ID NO: 1072)5′-UGUGGCAUUUAUUUGGAUAAAAUtc-3′ (SEQ ID NO: 695)3′-AUACACCGUAAAUAAACCUAUUUUAAG-5′ (SEQ ID NO: 317) HIF-1α-3598 Target:5′-TATGTGGCATTTATTTGGATAAAATTC-3′ (SEQ ID NO: 1073)5′-UGGCAUUUAUUUGGAUAAAAUUCtc-3′ (SEQ ID NO: 696)3′-ACACCGUAAAUAAACCUAUUUUAAGAG-5′ (SEQ ID NO: 318) HIF-1α-3600 Target:5′-TGTGGCATTTATTTGGATAAAATTCTC-3′ (SEQ ID NO: 1074)5′-GCAUUUAUUUGGAUAAAAUUCUCaa-3′ (SEQ ID NO: 697)3′-ACCGUAAAUAAACCUAUUUUAAGAGUU-5′ (SEQ ID NO: 319) HIF-1α-3602 Target:5′-TGGCATTTATTTGGATAAAATTCTCAA-3′ (SEQ ID NO: 1075)5′-AUUUAUUUGGAUAAAAUUCUCAAtt-3′ (SEQ ID NO: 698)3′-CGUAAAUAAACCUAUUUUAAGAGUUAA-5′ (SEQ ID NO: 320) HIF-1α-3604 Target:5′-GCATTTATTTGGATAAAATTCTCAATT-3′ (SEQ ID NO: 1076)5′-UUAUUUGGAUAAAAUUCUCAAUUca-3′ (SEQ ID NO: 699)3′-UAAAUAAACCUAUUUUAAGAGUUAAGU-5′ (SEQ ID NO: 321) HIF-1α-3606 Target:5′-ATTTATTTGGATAAAATTCTCAATTCA-3′ (SEQ ID NO: 1077)5′-AUUUGGAUAAAAUUCUCAAUUCAga-3′ (SEQ ID NO: 700)3′-AAUAAACCUAUUUUAAGAGUUAAGUCU-5′ (SEQ ID NO: 322) HIF-1α-3608 Target:5′-TTATTTGGATAAAATTCTCAATTCAGA-3′ (SEQ ID NO: 1078)5′-AUUUGGAUAAAAUUCUCAAUUCAga-3′ (SEQ ID NO: 701)3′-AAUAAACCUAUUUUAAGAGUUAAGUCU-5′ (SEQ ID NO: 323) HIF-1α-3608 Target:5′-TTATTTGGATAAAATTCTCAATTCAGA-3′ (SEQ ID NO: 1079)5′-UUGGAUAAAAUUCUCAAUUCAGAga-3′ (SEQ ID NO: 702)3′-UAAACCUAUUUUAAGAGUUAAGUCUCU-5′ (SEQ ID NO: 324) HIF-1α-3610 Target:5′-ATTTGGATAAAATTCTCAATTCAGAGA-3′ (SEQ ID NO: 1080)5′-GGAUAAAAUUCUCAAUUCAGAGAaa-3′ (SEQ ID NO: 703)3′-AACCUAUUUUAAGAGUUAAGUCUCUUU-5′ (SEQ ID NO: 325) HIF-1α-3612 Target:5′-TTGGATAAAATTCTCAATTCAGAGAAA-3′ (SEQ ID NO: 1081)5′-AUAAAAUUCUCAAUUCAGAGAAAtc-3′ (SEQ ID NO: 704)3′-CCUAUUUUAAGAGUUAAGUCUCUUUAG-5′ (SEQ ID NO: 326) HIF-1α-3614 Target:5′-GGATAAAATTCTCAATTCAGAGAAATC-3′ (SEQ ID NO: 1082)5′-AAAAUUCUCAAUUCAGAGAAAUCat-3′ (SEQ ID NO: 705)3′-UAUUUUAAGAGUUAAGUCUCUUUAGUA-5′ (SEQ ID NO: 327) HIF-1α-3616 Target:5′-ATAAAATTCTCAATTCAGAGAAATCAT-3′ (SEQ ID NO: 1083)5′-UCUGAUGUUUCUAUAGUCACUUUgc-3′ (SEQ ID NO: 706)3′-GUAGACUACAAAGAUAUCAGUGAAACG-5′ (SEQ ID NO: 328) HIF-1α-3640 Target:5′-CATCTGATGTTTCTATAGTCACTTTGC-3′ (SEQ ID NO: 1084)5′-GUUUCUAUAGUCACUUUGCCAGCtc-3′ (SEQ ID NO: 707)3′-UACAAAGAUAUCAGUGAAACGGUCGAG-5′ (SEQ ID NO: 329) HIF-1α-3646 Target:5′-ATGTTTCTATAGTCACTTTGCCAGCTC-3′ (SEQ ID NO: 1085)5′-UAUAGUCACUUUGCCAGCUCAAAag-3′ (SEQ ID NO: 708)3′-AGAUAUCAGUGAAACGGUCGAGUUUUC-5′ (SEQ ID NO: 330) HIF-1α-3651 Target:5′-TCTATAGTCACTTTGCCAGCTCAAAAG-3′ (SEQ ID NO: 1086)5′-CAAAAGAAAACAAUACCCUAUGUag-3′ (SEQ ID NO: 709)3′-GAGUUUUCUUUUGUUAUGGGAUACAUC-5′ (SEQ ID NO: 331) HIF-1α-3670 Target:5′-CTCAAAAGAAAACAATACCCTATGTAG-3′ (SEQ ID NO: 1087)5′-UUCUGCCUACCCUGUUGGUAUAAag-3′ (SEQ ID NO: 710)3′-ACAAGACGGAUGGGACAACCAUAUUUC-5′ (SEQ ID NO: 332) HIF-1α-3743 Target:5′-TGTTCTGCCTACCCTGTTGGTATAAAG-3′ (SEQ ID NO: 1088)5′-CUGCCUACCCUGUUGGUAUAAAGat-3′ (SEQ ID NO: 711)3′-AAGACGGAUGGGACAACCAUAUUUCUA-5′ (SEQ ID NO: 333) HIF-1α-3745 Target:5′-TTCTGCCTACCCTGTTGGTATAAAGAT-3′ (SEQ ID NO: 1089)5′-UGCCUACCCUGUUGGUAUAAAGAta-3′ (SEQ ID NO: 712)3′-AGACGGAUGGGACAACCAUAUUUCUAU-5′ (SEQ ID NO: 334) HIF-1α-3746 Target:5′-TCTGCCTACCCTGTTGGTATAAAGATA-3′ (SEQ ID NO: 1090)5′-CCUACCCUGUUGGUAUAAAGAUAtt-3′ (SEQ ID NO: 713)3′-ACGGAUGGGACAACCAUAUUUCUAUAA-5′ (SEQ ID NO: 335) HIF-1α-3748 Target:5′-TGCCTACCCTGTTGGTATAAAGATATT-3′ (SEQ ID NO: 1091)5′-CUACCCUGUUGGUAUAAAGAUAUtt-3′ (SEQ ID NO: 714)3′-CGGAUGGGACAACCAUAUUUCUAUAAA-5′ (SEQ ID NO: 336) HIF-1α-3749 Target:5′-GCCTACCCTGTTGGTATAAAGATATTT-3′ (SEQ ID NO: 1092)5′-CUGUUGGUAUAAAGAUAUUUUGAgc-3′ (SEQ ID NO: 715)3′-GGGACAACCAUAUUUCUAUAAAACUCG-5′ (SEQ ID NO: 337) HIF-1α-3754 Target:5′-CCCTGTTGGTATAAAGATATTTTGAGC-3′ (SEQ ID NO: 1093)5′-UUGGUAUAAAGAUAUUUUGAGCAga-3′ (SEQ ID NO: 716)3′-ACAACCAUAUUUCUAUAAAACUCGUCU-5′ (SEQ ID NO: 338) HIF-1α-3757 Target:5′-TGTTGGTATAAAGATATTTTGAGCAGA-3′ (SEQ ID NO: 1094)5′-AGAAAAAAAAAAUCAUGCAUUCUta-3′ (SEQ ID NO: 717)3′-GUUCUUUUUUUUUUAGUACGUAAGAAU-5′ (SEQ ID NO: 339) HIF-1α-3791 Target:5′-CAAGAAAAAAAAAATCATGCATTCTTA-3′ (SEQ ID NO: 1095)5′-UAUGUUAAUUUGCUCAAAAUACAat-3′ (SEQ ID NO: 718)3′-UCAUACAAUUAAACGAGUUUUAUGUUA-5′ (SEQ ID NO: 340) HIF-1α-3830 Target:5′-AGTATGTTAATTTGCTCAAAATACAAT-3′ (SEQ ID NO: 1096)5′-UUUUAUGCACUUUGUCGCUAUUAac-3′ (SEQ ID NO: 719)3′-CUAAAAUACGUGAAACAGCGAUAAUUG-5′ (SEQ ID NO: 341) HIF-1α-3861 Target:5′-GATTTTATGCACTTTGTCGCTATTAAC-3′ (SEQ ID NO: 1097)5′-UUAUGCACUUUGUCGCUAUUAACat-3′ (SEQ ID NO: 720)3′-AAAAUACGUGAAACAGCGAUAAUUGUA-5′ (SEQ ID NO: 342) HIF-1α-3863 Target:5′-TTTTATGCACTTTGTCGCTATTAACAT-3′ (SEQ ID NO: 1098)5′-AUGCACUUUGUCGCUAUUAACAUcc-3′ (SEQ ID NO: 721)3′-AAUACGUGAAACAGCGAUAAUUGUAGG-5′ (SEQ ID NO: 343) HIF-1α-3865 Target:5′-TTATGCACTTTGTCGCTATTAACATCC-3′ (SEQ ID NO: 1099)5′-GCACUUUGUCGCUAUUAACAUCCtt-3′ (SEQ ID NO: 722)3′-UACGUGAAACAGCGAUAAUUGUAGGAA-5′ (SEQ ID NO: 344) HIF-1α-3867 Target:5′-ATGCACTTTGTCGCTATTAACATCCTT-3′ (SEQ ID NO: 1100)5′-ACUUUGUCGCUAUUAACAUCCUUtt-3′ (SEQ ID NO: 723)3′-CGUGAAACAGCGAUAAUUGUAGGAAAA-5′ (SEQ ID NO: 345) HIF-1α-3869 Target:5′-GCACTTTGTCGCTATTAACATCCTTTT-3′ (SEQ ID NO: 1101)5′-UUUGUCGCUAUUAACAUCCUUUUtt-3′ (SEQ ID NO: 724)3′-UGAAACAGCGAUAAUUGUAGGAAAAAA-5′ (SEQ ID NO: 346) HIF-1α-3871 Target:5′-ACTTTGTCGCTATTAACATCCTTTTTT-3′ (SEQ ID NO: 1102)5′-UGUCGCUAUUAACAUCCUUUUUUtc-3′ (SEQ ID NO: 725)3′-AAACAGCGAUAAUUGUAGGAAAAAAAG-5′ (SEQ ID NO: 347) HIF-1α-3873 Target:5′-TTTGTCGCTATTAACATCCTTTTTTTC-3′ (SEQ ID NO: 1103)5′-UCGCUAUUAACAUCCUUUUUUUCat-3′ (SEQ ID NO: 726)3′-ACAGCGAUAAUUGUAGGAAAAAAAGUA-5′ (SEQ ID NO: 348) HIF-1α-3875 Target:5′-TGTCGCTATTAACATCCTTTTTTTCAT-3′ (SEQ ID NO: 1104)5′-GCUAUUAACAUCCUUUUUUUCAUgt-3′ (SEQ ID NO: 727)3′-AGCGAUAAUUGUAGGAAAAAAAGUACA-5′ (SEQ ID NO: 349) HIF-1α-3877 Target:5′-TCGCTATTAACATCCTTTTTTTCATGT-3′ (SEQ ID NO: 1105)5′-AUUAACAUCCUUUUUUUCAUGUAga-3′ (SEQ ID NO: 728)3′-GAUAAUUGUAGGAAAAAAAGUACAUCU-5′ (SEQ ID NO: 350) HIF-1α-3880 Target:5′-CTATTAACATCCTTTTTTTCATGTAGA-3′ (SEQ ID NO: 1106)5′-GAGUAAUUUUAGAAGCAUUAUUUta-3′ (SEQ ID NO: 729)3′-AACUCAUUAAAAUCUUCGUAAUAAAAU-5′ (SEQ ID NO: 351) HIF-1α-3916 Target:5′-TTGAGTAATTTTAGAAGCATTATTTTA-3′ (SEQ ID NO: 1107)5′-GUAAUUUUAGAAGCAUUAUUUUAgg-3′ (SEQ ID NO: 730)3′-CUCAUUAAAAUCUUCGUAAUAAAAUCC-5′ (SEQ ID NO: 352) HIF-1α-3918 Target:5′-GAGTAATTTTAGAAGCATTATTTTAGG-3′ (SEQ ID NO: 1108)5′-AAUUUUAGAAGCAUUAUUUUAGGaa-3′ (SEQ ID NO: 731)3′-CAUUAAAAUCUUCGUAAUAAAAUCCUU-5′ (SEQ ID NO: 353) HIF-1α-3920 Target:5′-GTAATTTTAGAAGCATTATTTTAGGAA-3′ (SEQ ID NO: 1109)5′-UUUUAGAAGCAUUAUUUUAGGAAta-3′ (SEQ ID NO: 732)3′-UUAAAAUCUUCGUAAUAAAAUCCUUAU-5′ (SEQ ID NO: 354) HIF-1α-3922 Target:5′-AATTTTAGAAGCATTATTTTAGGAATA-3′ (SEQ ID NO: 1110)5′-UUAGAAGCAUUAUUUUAGGAAUAta-3′ (SEQ ID NO: 733)3′-AAAAUCUUCGUAAUAAAAUCCUUAUAU-5′ (SEQ ID NO: 355) HIF-1α-3924 Target:5′-TTTTAGAAGCATTATTTTAGGAATATA-3′ (SEQ ID NO: 1111)5′-AGAAGCAUUAUUUUAGGAAUAUAta-3′ (SEQ ID NO: 734)3′-AAUCUUCGUAAUAAAAUCCUUAUAUAU-5′ (SEQ ID NO: 356) HIF-1α-3926 Target:5′-TTAGAAGCATTATTTTAGGAATATATA-3′ (SEQ ID NO: 1112)5′-AAGCAUUAUUUUAGGAAUAUAUAgt-3′ (SEQ ID NO: 735)3′-UCUUCGUAAUAAAAUCCUUAUAUAUCA-5′ (SEQ ID NO: 357) HIF-1α-3928 Target:5′-AGAAGCATTATTTTAGGAATATATAGT-3′ (SEQ ID NO: 1113)5′-GCAUUAUUUUAGGAAUAUAUAGUtg-3′ (SEQ ID NO: 736)3′-UUCGUAAUAAAAUCCUUAUAUAUCAAC-5′ (SEQ ID NO: 358) HIF-1α-3930 Target:5′-AAGCATTATTTTAGGAATATATAGTTG-3′ (SEQ ID NO: 1114)5′-UAAAUAUCUUGUUUUUUCUAUGUac-3′ (SEQ ID NO: 737)3′-UCAUUUAUAGAACAAAAAAGAUACAUG-5′ (SEQ ID NO: 359) HIF-1α-3961 Target:5′-AGTAAATATCTTGTTTTTTCTATGTAC-3′ (SEQ ID NO: 1115)5′-AUGUACAUUGUACAAAUUUUUCAtt-3′ (SEQ ID NO: 738)3′-GAUACAUGUAACAUGUUUAAAAAGUAA-5′ (SEQ ID NO: 360) HIF-1α-3980 Target:5′-CTATGTACATTGTACAAATTTTTCATT-3′ (SEQ ID NO: 1116)5′-UUCAUUCCUUUUGCUCUUUGUGGtt-3′ (SEQ ID NO: 739)3′-AAAAGUAAGGAAAACGAGAAACACCAA-5′ (SEQ ID NO: 361) HIF-1α-3999 Target:5′-TTTTCATTCCTTTTGCTCTTTGTGGTT-3′ (SEQ ID NO: 1117)5′-UCAUUCCUUUUGCUCUUUGUGGUtg-3′ (SEQ ID NO: 740)3′-AAAGUAAGGAAAACGAGAAACACCAAC-5′ (SEQ ID NO: 362) HIF-1α-4000 Target:5′-TTTCATTCCTTTTGCTCTTTGTGGTTG-3′ (SEQ ID NO: 1118)5′-CAUUCCUUUUGCUCUUUGUGGUUgg-3′ (SEQ ID NO: 741)3′-AAGUAAGGAAAACGAGAAACACCAACC-5′ (SEQ ID NO: 363) HIF-1α-4001 Target:5′-TTCATTCCTTTTGCTCTTTGTGGTTGG-3′ (SEQ ID NO: 1119)5′-UUCCUUUUGCUCUUUGUGGUUGGat-3′ (SEQ ID NO: 742)3′-GUAAGGAAAACGAGAAACACCAACCUA-5′ (SEQ ID NO: 364) HIF-1α-4003 Target:5′-CATTCCTTTTGCTCTTTGTGGTTGGAT-3′ (SEQ ID NO: 1120)5′-UCCUUUUGCUCUUUGUGGUUGGAtc-3′ (SEQ ID NO: 743)3′-UAAGGAAAACGAGAAACACCAACCUAG-5′ (SEQ ID NO: 365) HIF-1α-4004 Target:5′-ATTCCTTTTGCTCTTTGTGGTTGGATC-3′ (SEQ ID NO: 1121)5′-CCUUUUGCUCUUUGUGGUUGGAUct-3′ (SEQ ID NO: 744)3′-AAGGAAAACGAGAAACACCAACCUAGA-5′ (SEQ ID NO: 366) HIF-1α-4005 Target:5′-TTCCTTTTGCTCTTTGTGGTTGGATCT-3′ (SEQ ID NO: 1122)5′-CUUUUGCUCUUUGUGGUUGGAUCta-3′ (SEQ ID NO: 745)3′-AGGAAAACGAGAAACACCAACCUAGAU-5′ (SEQ ID NO: 367) HIF-1α-4006 Target:5′-TCCTTTTGCTCTTTGTGGTTGGATCTA-3′ (SEQ ID NO: 1123)5′-UUUUGCUCUUUGUGGUUGGAUCUaa-3′ (SEQ ID NO: 746)3′-GGAAAACGAGAAACACCAACCUAGAUU-5′ (SEQ ID NO: 368) HIF-1α-4007 Target:5′-CCTTTTGCTCTTTGTGGTTGGATCTAA-3′ (SEQ ID NO: 1124)5′-UUUGCUCUUUGUGGUUGGAUCUAac-3′ (SEQ ID NO: 747)3′-GAAAACGAGAAACACCAACCUAGAUUG-5′ (SEQ ID NO: 369) HIF-1α-4008 Target:5′-CTTTTGCTCTTTGTGGTTGGATCTAAC-3′ (SEQ ID NO: 1125)5′-UUGCUCUUUGUGGUUGGAUCUAAca-3′ (SEQ ID NO: 748)3′-AAAACGAGAAACACCAACCUAGAUUGU-5′ (SEQ ID NO: 370) HIF-1α-4009 Target:5′-TTTTGCTCTTTGTGGTTGGATCTAACA-3′ (SEQ ID NO: 1126)5′-UGCUCUUUGUGGUUGGAUCUAACac-3′ (SEQ ID NO: 749)3′-AAACGAGAAACACCAACCUAGAUUGUG-5′ (SEQ ID NO: 371) HIF-1α-4010 Target:5′-TTTGCTCTTTGTGGTTGGATCTAACAC-3′ (SEQ ID NO: 1127)5′-CUCUUUGUGGUUGGAUCUAACACta-3′ (SEQ ID NO: 750)3′-ACGAGAAACACCAACCUAGAUUGUGAU-5′ (SEQ ID NO: 372) HIF-1α-4012 Target:5′-TGCTCTTTGTGGTTGGATCTAACACTA-3′ (SEQ ID NO: 1128)5′-AUCAAAUAAACAUCUUCUGUGGAcc-3′ (SEQ ID NO: 751)3′-UGUAGUUUAUUUGUAGAAGACACCUGG-5′ (SEQ ID NO: 373) HIF-1α-4055 Target:5′-ACATCAAATAAACATCTTCTGTGGACC-3′ (SEQ ID NO: 1129)5′-CAAAUAAACAUCUUCUGUGGACCag-3′ (SEQ ID NO: 752)3′-UAGUUUAUUUGUAGAAGACACCUGGUC-5′ (SEQ ID NO: 374) HIF-1α-4057 Target:5′-ATCAAATAAACATCTTCTGTGGACCAG-3′ (SEQ ID NO: 1130)5′-AAUAAACAUCUUCUGUGGACCAGgc-3′ (SEQ ID NO: 753)3′-GUUUAUUUGUAGAAGACACCUGGUCCG-5′ (SEQ ID NO: 375) HIF-1α-4059 Target:5′-CAAATAAACATCTTCTGTGGACCAGGC-3′ (SEQ ID NO: 1131)5′-UAAACAUCUUCUGUGGACCAGGCaa-3′ (SEQ ID NO: 754)3′-UUAUUUGUAGAAGACACCUGGUCCGUU-5′ (SEQ ID NO: 376) HIF-1α-4061 Target:5′-AATAAACATCTTCTGTGGACCAGGCAA-3′ (SEQ ID NO: 1132)5′-AACAUCUUCUGUGGACCAGGCAAaa-3′ (SEQ ID NO: 755)3′-AUUUGUAGAAGACACCUGGUCCGUUUU-5′ (SEQ ID NO: 377) HIF-1α-4063 Target:5′-TAAACATCTTCTGTGGACCAGGCAAAA-3′ (SEQ ID NO: 1133)5′-CAUCUUCUGUGGACCAGGCAAAAaa-3′ (SEQ ID NO: 756)3′-UUGUAGAAGACACCUGGUCCGUUUUUU-5′ (SEQ ID NO: 378) HIF-1α-4065 Target:5′-AACATCTTCTGTGGACCAGGCAAAAAA-3′ (SEQ ID NO: 1134)5′-AGAUAAGUUCUGAACGUCGAAAAga-3′ (SEQ ID NO: 2620)3′-UUUCUAUUCAAGACUUGCAGCUUUUCU-5′ (SEQ ID NO: 2096) HIF-1α-463 Target:5′-AAAGATAAGTTCTGAACGTCGAAAAGA-3′ (SEQ ID NO: 3144)5′-UAAGUUCUGAACGUCGAAAAGAAaa-3′ (SEQ ID NO: 2621)3′-CUAUUCAAGACUUGCAGCUUUUCUUUU-5′ (SEQ ID NO: 2097) HIF-1α-466 Target:5′-GATAAGTTCTGAACGTCGAAAAGAAAA-3′ (SEQ ID NO: 3145)5′-AGUUCUGAACGUCGAAAAGAAAAgt-3′ (SEQ ID NO: 2622)3′-AUUCAAGACUUGCAGCUUUUCUUUUCA-5′ (SEQ ID NO: 2098) HIF-1α-468 Target:5′-TAAGTTCTGAACGTCGAAAAGAAAAGT-3′ (SEQ ID NO: 3146)5′-CUGAACGUCGAAAAGAAAAGUCUcg-3′ (SEQ ID NO: 2623)3′-AAGACUUGCAGCUUUUCUUUUCAGAGC-5′ (SEQ ID NO: 2099) HIF-1α-472 Target:5′-TTCTGAACGTCGAAAAGAAAAGTCTCG-3′ (SEQ ID NO: 3147)5′-CGAAAAGAAAAGUCUCGAGAUGCag-3′ (SEQ ID NO: 2624)3′-CAGCUUUUCUUUUCAGAGCUCUACGUC-5′ (SEQ ID NO: 2100) HIF-1α-480 Target:5′-GTCGAAAAGAAAAGTCTCGAGATGCAG-3′ (SEQ ID NO: 3148)5′-GAAAAGAAAAGUCUCGAGAUGCAgc-3′ (SEQ ID NO: 2625)3′-AGCUUUUCUUUUCAGAGCUCUACGUCG-5′ (SEQ ID NO: 2101) HIF-1α-481 Target:5′-TCGAAAAGAAAAGTCTCGAGATGCAGC-3′ (SEQ ID NO: 3149)5′-CGAAGUAAAGAAUCUGAAGUUUUtt-3′ (SEQ ID NO: 2626)3′-CCGCUUCAUUUCUUAGACUUCAAAAAA-5′ (SEQ ID NO: 2102) HIF-1α-516 Target:5′-GGCGAAGTAAAGAATCTGAAGTTTTTT-3′ (SEQ ID NO: 3150)5′-GAAGUAAAGAAUCUGAAGUUUUUta-3′ (SEQ ID NO: 2627)3′-CGCUUCAUUUCUUAGACUUCAAAAAAU-5′ (SEQ ID NO: 2103) HIF-1α-517 Target:5′-GCGAAGTAAAGAATCTGAAGTTTTTTA-3′ (SEQ ID NO: 3151)5′-AGUAAAGAAUCUGAAGUUUUUUAtg-3′ (SEQ ID NO: 2628)3′-CUUCAUUUCUUAGACUUCAAAAAAUAC-5′ (SEQ ID NO: 2104) HIF-1α-519 Target:5′-GAAGTAAAGAATCTGAAGTTTTTTATG-3′ (SEQ ID NO: 3152)5′-GUAAAGAAUCUGAAGUUUUUUAUga-3′ (SEQ ID NO: 2629)3′-UUCAUUUCUUAGACUUCAAAAAAUACU-5′ (SEQ ID NO: 2105) HIF-1α-520 Target:5′-AAGTAAAGAATCTGAAGTTTTTTATGA-3′ (SEQ ID NO: 3153)5′-AAAGAAUCUGAAGUUUUUUAUGAgc-3′ (SEQ ID NO: 2630)3′-CAUUUCUUAGACUUCAAAAAAUACUCG-5′ (SEQ ID NO: 2106) HIF-1α-522 Target:5′-GTAAAGAATCTGAAGTTTTTTATGAGC-3′ (SEQ ID NO: 3154)5′-CUGAAGUUUUUUAUGAGCUUGCUca-3′ (SEQ ID NO: 2631)3′-UAGACUUCAAAAAAUACUCGAACGAGU-5′ (SEQ ID NO: 2107) HIF-1α-529 Target:5′-ATCTGAAGTTTTTTATGAGCTTGCTCA-3′ (SEQ ID NO: 3155)5′-GUUGCCACUUCCACAUAAUGUGAgt-3′ (SEQ ID NO: 2632)3′-GUCAACGGUGAAGGUGUAUUACACUCA-5′ (SEQ ID NO: 2108) HIF-1α-557 Target:5′-CAGTTGCCACTTCCACATAATGTGAGT-3′ (SEQ ID NO: 3156)5′-GUGAGUUCGCAUCUUGAUAAGGCct-3′ (SEQ ID NO: 2633)3′-UACACUCAAGCGUAGAACUAUUCCGGA-5′ (SEQ ID NO: 2109) HIF-1α-576 Target:5′-ATGTGAGTTCGCATCTTGATAAGGCCT-3′ (SEQ ID NO: 3157)5′-GAGGCUUACCAUCAGCUAUUUGCgt-3′ (SEQ ID NO: 2634)3′-UACUCCGAAUGGUAGUCGAUAAACGCA-5′ (SEQ ID NO: 2110) HIF-1α-608 Target:5′-ATGAGGCTTACCATCAGCTATTTGCGT-3′ (SEQ ID NO: 3158)5′-AGGAAACUUCUGGAUGCUGGUGAtt-3′ (SEQ ID NO: 2635)3′-ACUCCUUUGAAGACCUACGACCACUAA-5′ (SEQ ID NO: 2111) HIF-1α-636 Target:5′-TGAGGAAACTTCTGGATGCTGGTGATT-3′ (SEQ ID NO: 3159)5′-CUGGUGAUUUGGAUAUUGAAGAUga-3′ (SEQ ID NO: 2636)3′-ACGACCACUAAACCUAUAACUUCUACU-5′ (SEQ ID NO: 2112) HIF-1α-652 Target:5′-TGCTGGTGATTTGGATATTGAAGATGA-3′ (SEQ ID NO: 3160)5′-GGUGAUUUGGAUAUUGAAGAUGAca-3′ (SEQ ID NO: 2637)3′-GACCACUAAACCUAUAACUUCUACUGU-5′ (SEQ ID NO: 2113) HIF-1α-654 Target:5′-CTGGTGATTTGGATATTGAAGATGACA-3′ (SEQ ID NO: 3161)5′-UUGGAUAUUGAAGAUGACAUGAAag-3′ (SEQ ID NO: 2638)3′-UAAACCUAUAACUUCUACUGUACUUUC-5′ (SEQ ID NO: 2114) HIF-1α-660 Target:5′-ATTTGGATATTGAAGATGACATGAAAG-3′ (SEQ ID NO: 3162)5′-UGGAUAUUGAAGAUGACAUGAAAgc-3′ (SEQ ID NO: 2639)3′-AAACCUAUAACUUCUACUGUACUUUCG-5′ (SEQ ID NO: 2115) HIF-1α-661 Target:5′-TTTGGATATTGAAGATGACATGAAAGC-3′ (SEQ ID NO: 3163)5′-GAUAUUGAAGAUGACAUGAAAGCac-3′ (SEQ ID NO: 2640)3′-ACCUAUAACUUCUACUGUACUUUCGUG-5′ (SEQ ID NO: 2116) HIF-1α-663 Target:5′-TGGATATTGAAGATGACATGAAAGCAC-3′ (SEQ ID NO: 3164)5′-AUAUUGAAGAUGACAUGAAAGCAca-3′ (SEQ ID NO: 2641)3′-CCUAUAACUUCUACUGUACUUUCGUGU-5′ (SEQ ID NO: 2117) HIF-1α-664 Target:5′-GGATATTGAAGATGACATGAAAGCACA-3′ (SEQ ID NO: 3165)5′-AGAUGACAUGAAAGCACAGAUGAat-3′ (SEQ ID NO: 2642)3′-CUUCUACUGUACUUUCGUGUCUACUUA-5′ (SEQ ID NO: 2118) HIF-1α-671 Target:5′-GAAGATGACATGAAAGCACAGATGAAT-3′ (SEQ ID NO: 3166)5′-GAUGACAUGAAAGCACAGAUGAAtt-3′ (SEQ ID NO: 2643)3′-UUCUACUGUACUUUCGUGUCUACUUAA-5′ (SEQ ID NO: 2119) HIF-1α-672 Target:5′-AAGATGACATGAAAGCACAGATGAATT-3′ (SEQ ID NO: 3167)5′-AAAGCACAGAUGAAUUGCUUUUAtt-3′ (SEQ ID NO: 2644)3′-ACUUUCGUGUCUACUUAACGAAAAUAA-5′ (SEQ ID NO: 2120) HIF-1α-681 Target:5′-TGAAAGCACAGATGAATTGCTTTTATT-3′ (SEQ ID NO: 3168)5′-CAGAUGAAUUGCUUUUAUUUGAAag-3′ (SEQ ID NO: 2645)3′-GUGUCUACUUAACGAAAAUAAACUUUC-5′ (SEQ ID NO: 2121) HIF-1α-687 Target:5′-CACAGATGAATTGCTTTTATTTGAAAG-3′ (SEQ ID NO: 3169)5′-AGAUGAAUUGCUUUUAUUUGAAAgc-3′ (SEQ ID NO: 2646)3′-UGUCUACUUAACGAAAAUAAACUUUCG-5′ (SEQ ID NO: 2122) HIF-1α-688 Target:5′-ACAGATGAATTGCTTTTATTTGAAAGC-3′ (SEQ ID NO: 3170)5′-UUAUUUGAAAGCCUUGGAUGGUUtt-3′ (SEQ ID NO: 2647)3′-AAAAUAAACUUUCGGAACCUACCAAAA-5′ (SEQ ID NO: 2123) HIF-1α-701 Target:5′-TTTTATTTGAAAGCCTTGGATGGTTTT-3′ (SEQ ID NO: 3171)5′-UAUUUGAAAGCCUUGGAUGGUUUtg-3′ (SEQ ID NO: 2648)3′-AAAUAAACUUUCGGAACCUACCAAAAC-5′ (SEQ ID NO: 2124) HIF-1α-702 Target:5′-TTTATTTGAAAGCCTTGGATGGTTTTG-3′ (SEQ ID NO: 3172)5′-AAAGCCUUGGAUGGUUUUGUUAUgg-3′ (SEQ ID NO: 2649)3′-ACUUUCGGAACCUACCAAAACAAUACC-5′ (SEQ ID NO: 2125) HIF-1α-708 Target:5′-TGAAAGCCTTGGATGGTTTTGTTATGG-3′ (SEQ ID NO: 3173)5′-UUUGUUAUGGUUCUCACAGAUGAtg-3′ (SEQ ID NO: 2650)3′-CAAAACAAUACCAAGAGUGUCUACUAC-5′ (SEQ ID NO: 2126) HIF-1α-723 Target:5′-GTTTTGTTATGGTTCTCACAGATGATG-3′ (SEQ ID NO: 3174)5′-AUGGUUCUCACAGAUGAUGGUGAca-3′ (SEQ ID NO: 2651)3′-AAUACCAAGAGUGUCUACUACCACUGU-5′ (SEQ ID NO: 2127) HIF-1α-729 Target:5′-TTATGGTTCTCACAGATGATGGTGACA-3′ (SEQ ID NO: 3175)5′-UGGUUCUCACAGAUGAUGGUGACat-3′ (SEQ ID NO: 2652)3′-AUACCAAGAGUGUCUACUACCACUGUA-5′ (SEQ ID NO: 2128) HIF-1α-730 Target:5′-TATGGTTCTCACAGATGATGGTGACAT-3′ (SEQ ID NO: 3176)5′-CAGAUGAUGGUGACAUGAUUUACat-3′ (SEQ ID NO: 2653)3′-GUGUCUACUACCACUGUACUAAAUGUA-5′ (SEQ ID NO: 2129) HIF-1α-739 Target:5′-CACAGATGATGGTGACATGATTTACAT-3′ (SEQ ID NO: 3177)5′-GAUGGUGACAUGAUUUACAUUUCtg-3′ (SEQ ID NO: 2654)3′-UACUACCACUGUACUAAAUGUAAAGAC-5′ (SEQ ID NO: 2130) HIF-1α-744 Target:5′-ATGATGGTGACATGATTTACATTTCTG-3′ (SEQ ID NO: 3178)5′-AUGGUGACAUGAUUUACAUUUCUga-3′ (SEQ ID NO: 2655)3′-ACUACCACUGUACUAAAUGUAAAGACU-5′ (SEQ ID NO: 2131) HIF-1α-745 Target:5′-TGATGGTGACATGATTTACATTTCTGA-3′ (SEQ ID NO: 3179)5′-AUGAUUUACAUUUCUGAUAAUGUga-3′ (SEQ ID NO: 2656)3′-UGUACUAAAUGUAAAGACUAUUACACU-5′ (SEQ ID NO: 2132) HIF-1α-753 Target:5′-ACATGATTTACATTTCTGATAATGTGA-3′ (SEQ ID NO: 3180)5′-GAUUUACAUUUCUGAUAAUGUGAac-3′ (SEQ ID NO: 2657)3′-UACUAAAUGUAAAGACUAUUACACUUG-5′ (SEQ ID NO: 2133) HIF-1α-755 Target:5′-ATGATTTACATTTCTGATAATGTGAAC-3′ (SEQ ID NO: 3181)5′-UUUACAUUUCUGAUAAUGUGAACaa-3′ (SEQ ID NO: 2658)3′-CUAAAUGUAAAGACUAUUACACUUGUU-5′ (SEQ ID NO: 2134) HIF-1α-757 Target:5′-GATTTACATTTCTGATAATGTGAACAA-3′ (SEQ ID NO: 3182)5′-AUUUCUGAUAAUGUGAACAAAUAca-3′ (SEQ ID NO: 2659)3′-UGUAAAGACUAUUACACUUGUUUAUGU-5′ (SEQ ID NO: 2135) HIF-1α-762 Target:5′-ACATTTCTGATAATGTGAACAAATACA-3′ (SEQ ID NO: 3183)5′-UAAUGUGAACAAAUACAUGGGAUta-3′ (SEQ ID NO: 2660)3′-CUAUUACACUUGUUUAUGUACCCUAAU-5′ (SEQ ID NO: 2136) HIF-1α-770 Target:5′-GATAATGTGAACAAATACATGGGATTA-3′ (SEQ ID NO: 3184)5′-AAUGUGAACAAAUACAUGGGAUUaa-3′ (SEQ ID NO: 2661)3′-UAUUACACUUGUUUAUGUACCCUAAUU-5′ (SEQ ID NO: 2137) HIF-1α-771 Target:5′-ATAATGTGAACAAATACATGGGATTAA-3′ (SEQ ID NO: 3185)5′-AUGUGAACAAAUACAUGGGAUUAac-3′ (SEQ ID NO: 2662)3′-AUUACACUUGUUUAUGUACCCUAAUUG-5′ (SEQ ID NO: 2138) HIF-1α-772 Target:5′-TAATGTGAACAAATACATGGGATTAAC-3′ (SEQ ID NO: 3186)5′-UGUGAACAAAUACAUGGGAUUAAct-3′ (SEQ ID NO: 2663)3′-UUACACUUGUUUAUGUACCCUAAUUGA-5′ (SEQ ID NO: 2139) HIF-1α-773 Target:5′-AATGTGAACAAATACATGGGATTAACT-3′ (SEQ ID NO: 3187)5′-GUGAACAAAUACAUGGGAUUAACtc-3′ (SEQ ID NO: 2664)3′-UACACUUGUUUAUGUACCCUAAUUGAG-5′ (SEQ ID NO: 2140) HIF-1α-774 Target:5′-ATGTGAACAAATACATGGGATTAACTC-3′ (SEQ ID NO: 3188)5′-UGAACAAAUACAUGGGAUUAACUca-3′ (SEQ ID NO: 2665)3′-ACACUUGUUUAUGUACCCUAAUUGAGU-5′ (SEQ ID NO: 2141) HIF-1α-775 Target:5′-TGTGAACAAATACATGGGATTAACTCA-3′ (SEQ ID NO: 3189)5′-CAUGGGAUUAACUCAGUUUGAACta-3′ (SEQ ID NO: 2666)3′-AUGUACCCUAAUUGAGUCAAACUUGAU-5′ (SEQ ID NO: 2142) HIF-1α-785 Target:5′-TACATGGGATTAACTCAGTTTGAACTA-3′ (SEQ ID NO: 3190)5′-AUGGGAUUAACUCAGUUUGAACUaa-3′ (SEQ ID NO: 2667)3′-UGUACCCUAAUUGAGUCAAACUUGAUU-5′ (SEQ ID NO: 2143) HIF-1α-786 Target:5′-ACATGGGATTAACTCAGTTTGAACTAA-3′ (SEQ ID NO: 3191)5′-UUUGAACUAACUGGACACAGUGUgt-3′ (SEQ ID NO: 2668)3′-UCAAACUUGAUUGACCUGUGUCACACA-5′ (SEQ ID NO: 2144) HIF-1α-801 Target:5′-AGTTTGAACTAACTGGACACAGTGTGT-3′ (SEQ ID NO: 3192)5′-CUGGACACAGUGUGUUUGAUUUUac-3′ (SEQ ID NO: 2669)3′-UUGACCUGUGUCACACAAACUAAAAUG-5′ (SEQ ID NO: 2145) HIF-1α-811 Target:5′-AACTGGACACAGTGTGTTTGATTTTAC-3′ (SEQ ID NO: 3193)5′-UGGACACAGUGUGUUUGAUUUUAct-3′ (SEQ ID NO: 2670)3′-UGACCUGUGUCACACAAACUAAAAUGA-5′ (SEQ ID NO: 2146) HIF-1α-812 Target:5′-ACTGGACACAGTGTGTTTGATTTTACT-3′ (SEQ ID NO: 3194)5′-UUUGAUUUUACUCAUCCAUGUGAcc-3′ (SEQ ID NO: 2671)3′-ACAAACUAAAAUGAGUAGGUACACUGG-5′ (SEQ ID NO: 2147) HIF-1α-825 Target:5′-TGTTTGATTTTACTCATCCATGTGACC-3′ (SEQ ID NO: 3195)5′-UGAUUUUACUCAUCCAUGUGACCat-3′ (SEQ ID NO: 2672)3′-AAACUAAAAUGAGUAGGUACACUGGUA-5′ (SEQ ID NO: 2148) HIF-1α-827 Target:5′-TTTGATTTTACTCATCCATGTGACCAT-3′ (SEQ ID NO: 3196)5′-CAUGUGACCAUGAGGAAAUGAGAga-3′ (SEQ ID NO: 2673)3′-AGGUACACUGGUACUCCUUUACUCUCU-5′ (SEQ ID NO: 2149) HIF-1α-841 Target:5′-TCCATGTGACCATGAGGAAATGAGAGA-3′ (SEQ ID NO: 3197)5′-UGUGACCAUGAGGAAAUGAGAGAaa-3′ (SEQ ID NO: 2674)3′-GUACACUGGUACUCCUUUACUCUCUUU-5′ (SEQ ID NO: 2150) HIF-1α-843 Target:5′-CATGTGACCATGAGGAAATGAGAGAAA-3′ (SEQ ID NO: 3198)5′-CAUGAGGAAAUGAGAGAAAUGCUta-3′ (SEQ ID NO: 2675)3′-UGGUACUCCUUUACUCUCUUUACGAAU-5′ (SEQ ID NO: 2151) HIF-1α-849 Target:5′-ACCATGAGGAAATGAGAGAAATGCTTA-3′ (SEQ ID NO: 3199)5′-AGAGAAAUGCUUACACACAGAAAtg-3′ (SEQ ID NO: 2676)3′-ACUCUCUUUACGAAUGUGUGUCUUUAC-5′ (SEQ ID NO: 2152) HIF-1α-861 Target:5′-TGAGAGAAATGCTTACACACAGAAATG-3′ (SEQ ID NO: 3200)5′-AAAUGCUUACACACAGAAAUGGCct-3′ (SEQ ID NO: 2677)3′-UCUUUACGAAUGUGUGUCUUUACCGGA-5′ (SEQ ID NO: 2153) HIF-1α-865 Target:5′-AGAAATGCTTACACACAGAAATGGCCT-3′ (SEQ ID NO: 3201)5′-AAUGCUUACACACAGAAAUGGCCtt-3′ (SEQ ID NO: 2678)3′-CUUUACGAAUGUGUGUCUUUACCGGAA-5′ (SEQ ID NO: 2154) HIF-1α-866 Target:5′-GAAATGCTTACACACAGAAATGGCCTT-3′ (SEQ ID NO: 3202)5′-GAAAUGGCCUUGUGAAAAAGGGUaa-3′ (SEQ ID NO: 2679)3′-GUCUUUACCGGAACACUUUUUCCCAUU-5′ (SEQ ID NO: 2155) HIF-1α-880 Target:5′-CAGAAATGGCCTTGTGAAAAAGGGTAA-3′ (SEQ ID NO: 3203)5′-AAAUGGCCUUGUGAAAAAGGGUAaa-3′ (SEQ ID NO: 2680)3′-UCUUUACCGGAACACUUUUUCCCAUUU-5′ (SEQ ID NO: 2156) HIF-1α-881 Target:5′-AGAAATGGCCTTGTGAAAAAGGGTAAA-3′ (SEQ ID NO: 3204)5′-AAUGGCCUUGUGAAAAAGGGUAAag-3′ (SEQ ID NO: 2681)3′-CUUUACCGGAACACUUUUUCCCAUUUC-5′ (SEQ ID NO: 2157) HIF-1α-882 Target:5′-GAAATGGCCTTGTGAAAAAGGGTAAAG-3′ (SEQ ID NO: 3205)5′-AUGGCCUUGUGAAAAAGGGUAAAga-3′ (SEQ ID NO: 2682)3′-UUUACCGGAACACUUUUUCCCAUUUCU-5′ (SEQ ID NO: 2158) HIF-1α-883 Target:5′-AAATGGCCTTGTGAAAAAGGGTAAAGA-3′ (SEQ ID NO: 3206)5′-CUUGUGAAAAAGGGUAAAGAACAaa-3′ (SEQ ID NO: 2683)3′-CGGAACACUUUUUCCCAUUUCUUGUUU-5′ (SEQ ID NO: 2159) HIF-1α-888 Target:5′-GCCTTGTGAAAAAGGGTAAAGAACAAA-3′ (SEQ ID NO: 3207)5′-AAGAACAAAACACACAGCGAAGCtt-3′ (SEQ ID NO: 2684)3′-AUUUCUUGUUUUGUGUGUCGCUUCGAA-5′ (SEQ ID NO: 2160) HIF-1α-904 Target:5′-TAAAGAACAAAACACACAGCGAAGCTT-3′ (SEQ ID NO: 3208)5′-CUUUUUUCUCAGAAUGAAGUGUAcc-3′ (SEQ ID NO: 2685)3′-UCGAAAAAAGAGUCUUACUUCACAUGG-5′ (SEQ ID NO: 2161) HIF-1α-926 Target:5′-AGCTTTTTTCTCAGAATGAAGTGTACC-3′ (SEQ ID NO: 3209)5′-UUUUUCUCAGAAUGAAGUGUACCct-3′ (SEQ ID NO: 2686)3′-GAAAAAAGAGUCUUACUUCACAUGGGA-5′ (SEQ ID NO: 2162) HIF-1α-928 Target:5′-CTTTTTTCTCAGAATGAAGTGTACCCT-3′ (SEQ ID NO: 3210)5′-AAUGAAGUGUACCCUAACUAGCCga-3′ (SEQ ID NO: 2687)3′-UCUUACUUCACAUGGGAUUGAUCGGCU-5′ (SEQ ID NO: 2163) HIF-1α-938 Target:5′-AGAATGAAGTGTACCCTAACTAGCCGA-3′ (SEQ ID NO: 3211)5′-AGGAAGAACUAUGAACAUAAAGUct-3′ (SEQ ID NO: 2688)3′-GCUCCUUCUUGAUACUUGUAUUUCAGA-5′ (SEQ ID NO: 2164) HIF-1α-962 Target:5′-CGAGGAAGAACTATGAACATAAAGTCT-3′ (SEQ ID NO: 3212)5′-GGAAGAACUAUGAACAUAAAGUCtg-3′ (SEQ ID NO: 2689)3′-CUCCUUCUUGAUACUUGUAUUUCAGAC-5′ (SEQ ID NO: 2165) HIF-1α-963 Target:5′-GAGGAAGAACTATGAACATAAAGTCTG-3′ (SEQ ID NO: 3213)5′-GAAGAACUAUGAACAUAAAGUCUgc-3′ (SEQ ID NO: 2690)3′-UCCUUCUUGAUACUUGUAUUUCAGACG-5′ (SEQ ID NO: 2166) HIF-1α-964 Target:5′-AGGAAGAACTATGAACATAAAGTCTGC-3′ (SEQ ID NO: 3214)5′-CAGGCCACAUUCACGUAUAUGAUac-3′ (SEQ ID NO: 2691)3′-GUGUCCGGUGUAAGUGCAUAUACUAUG-5′ (SEQ ID NO: 2167) HIF-1α-1012 Target:5′-CACAGGCCACATTCACGTATATGATAC-3′ (SEQ ID NO: 3215)5′-UGGGUAUAAGAAACCACCUAUGAcc-3′ (SEQ ID NO: 2692)3′-ACACCCAUAUUCUUUGGUGGAUACUGG-5′ (SEQ ID NO: 2168) HIF-1α-1058 Target:5′-TGTGGGTATAAGAAACCACCTATGACC-3′ (SEQ ID NO: 3216)5′-GGGUAUAAGAAACCACCUAUGACct-3′ (SEQ ID NO: 2693)3′-CACCCAUAUUCUUUGGUGGAUACUGGA-5′ (SEQ ID NO: 2169) HIF-1α-1059 Target:5′-GTGGGTATAAGAAACCACCTATGACCT-3′ (SEQ ID NO: 3217)5′-AUAUUGAAAUUCCUUUAGAUAGCaa-3′ (SEQ ID NO: 2694)3′-UUUAUAACUUUAAGGAAAUCUAUCGUU-5′ (SEQ ID NO: 2170) HIF-1α-1123 Target:5′-AAATATTGAAATTCCTTTAGATAGCAA-3′ (SEQ ID NO: 3218)5′-AAAUUCCUUUAGAUAGCAAGACUtt-3′ (SEQ ID NO: 2695)3′-ACUUUAAGGAAAUCUAUCGUUCUGAAA-5′ (SEQ ID NO: 2171) HIF-1α-1129 Target:5′-TGAAATTCCTTTAGATAGCAAGACTTT-3′ (SEQ ID NO: 3219)5′-GAUAUGAAAUUUUCUUAUUGUGAtg-3′ (SEQ ID NO: 2696)3′-ACCUAUACUUUAAAAGAAUAACACUAC-5′ (SEQ ID NO: 2172) HIF-1α-1173 Target:5′-TGGATATGAAATTTTCTTATTGTGATG-3′ (SEQ ID NO: 3220)5′-AUGAAAUUUUCUUAUUGUGAUGAaa-3′ (SEQ ID NO: 2697)3′-UAUACUUUAAAAGAAUAACACUACUUU-5′ (SEQ ID NO: 2173) HIF-1α-1176 Target:5′-ATATGAAATTTTCTTATTGTGATGAAA-3′ (SEQ ID NO: 3221)5′-UGAAAUUUUCUUAUUGUGAUGAAag-3′ (SEQ ID NO: 2698)3′-AUACUUUAAAAGAAUAACACUACUUUC-5′ (SEQ ID NO: 2174) HIF-1α-1177 Target:5′-TATGAAATTTTCTTATTGTGATGAAAG-3′ (SEQ ID NO: 3222)5′-GAAAUUUUCUUAUUGUGAUGAAAga-3′ (SEQ ID NO: 2699)3′-UACUUUAAAAGAAUAACACUACUUUCU-5′ (SEQ ID NO: 2175) HIF-1α-1178 Target:5′-ATGAAATTTTCTTATTGTGATGAAAGA-3′ (SEQ ID NO: 3223)5′-AAUUUUCUUAUUGUGAUGAAAGAat-3′ (SEQ ID NO: 2700)3′-CUUUAAAAGAAUAACACUACUUUCUUA-5′ (SEQ ID NO: 2176) HIF-1α-1180 Target:5′-GAAATTTTCTTATTGTGATGAAAGAAT-3′ (SEQ ID NO: 3224)5′-AUUUUCUUAUUGUGAUGAAAGAAtt-3′ (SEQ ID NO: 2701)3′-UUUAAAAGAAUAACACUACUUUCUUAA-5′ (SEQ ID NO: 2177) HIF-1α-1181 Target:5′-AAATTTTCTTATTGTGATGAAAGAATT-3′ (SEQ ID NO: 3225)5′-UUUUCUUAUUGUGAUGAAAGAAUta-3′ (SEQ ID NO: 2702)3′-UUAAAAGAAUAACACUACUUUCUUAAU-5′ (SEQ ID NO: 2178) HIF-1α-1182 Target:5′-AATTTTCTTATTGTGATGAAAGAATTA-3′ (SEQ ID NO: 3226)5′-CUUAUUGUGAUGAAAGAAUUACCga-3′ (SEQ ID NO: 2703)3′-AAGAAUAACACUACUUUCUUAAUGGCU-5′ (SEQ ID NO: 2179) HIF-1α-1186 Target:5′-TTCTTATTGTGATGAAAGAATTACCGA-3′ (SEQ ID NO: 3227)5′-UGUGAUGAAAGAAUUACCGAAUUga-3′ (SEQ ID NO: 2704)3′-UAACACUACUUUCUUAAUGGCUUAACU-5′ (SEQ ID NO: 2180) HIF-1α-1191 Target:5′-ATTGTGATGAAAGAATTACCGAATTGA-3′ (SEQ ID NO: 3228)5′-UGAUGAAAGAAUUACCGAAUUGAtg-3′ (SEQ ID NO: 2705)3′-ACACUACUUUCUUAAUGGCUUAACUAC-5′ (SEQ ID NO: 2181) HIF-1α-1193 Target:5′-TGTGATGAAAGAATTACCGAATTGATG-3′ (SEQ ID NO: 3229)5′-AAAGAAUUACCGAAUUGAUGGGAta-3′ (SEQ ID NO: 2706)3′-ACUUUCUUAAUGGCUUAACUACCCUAU-5′ (SEQ ID NO: 2182) HIF-1α-1198 Target:5′-TGAAAGAATTACCGAATTGATGGGATA-3′ (SEQ ID NO: 3230)5′-AAGAAUUACCGAAUUGAUGGGAUat-3′ (SEQ ID NO: 2707)3′-CUUUCUUAAUGGCUUAACUACCCUAUA-5′ (SEQ ID NO: 2183) HIF-1α-1199 Target:5′-GAAAGAATTACCGAATTGATGGGATAT-3′ (SEQ ID NO: 3231)5′-AGAAUUACCGAAUUGAUGGGAUAtg-3′ (SEQ ID NO: 2708)3′-UUUCUUAAUGGCUUAACUACCCUAUAC-5′ (SEQ ID NO: 2184) HIF-1α-1200 Target:5′-AAAGAATTACCGAATTGATGGGATATG-3′ (SEQ ID NO: 3232)5′-GAAUUACCGAAUUGAUGGGAUAUga-3′ (SEQ ID NO: 2709)3′-UUCUUAAUGGCUUAACUACCCUAUACU-5′ (SEQ ID NO: 2185) HIF-1α-1201 Target:5′-AAGAATTACCGAATTGATGGGATATGA-3′ (SEQ ID NO: 3233)5′-AUGGGAUAUGAGCCAGAAGAACUtt-3′ (SEQ ID NO: 2710)3′-ACUACCCUAUACUCGGUCUUCUUGAAA-5′ (SEQ ID NO: 2186) HIF-1α-1215 Target:5′-TGATGGGATATGAGCCAGAAGAACTTT-3′ (SEQ ID NO: 3234)5′-AUGAGCCAGAAGAACUUUUAGGCcg-3′ (SEQ ID NO: 2711)3′-UAUACUCGGUCUUCUUGAAAAUCCGGC-5′ (SEQ ID NO: 2187) HIF-1α-1222 Target:5′-ATATGAGCCAGAAGAACTTTTAGGCCG-3′ (SEQ ID NO: 3235)5′-UAGGCCGCUCAAUUUAUGAAUAUta-3′ (SEQ ID NO: 2712)3′-AAAUCCGGCGAGUUAAAUACUUAUAAU-5′ (SEQ ID NO: 2188) HIF-1α-1240 Target:5′-TTTAGGCCGCTCAATTTATGAATATTA-3′ (SEQ ID NO: 3236)5′-UAUGAAUAUUAUCAUGCUUUGGAct-3′ (SEQ ID NO: 2713)3′-AAAUACUUAUAAUAGUACGAAACCUGA-5′ (SEQ ID NO: 2189) HIF-1α-1254 Target:5′-TTTATGAATATTATCATGCTTTGGACT-3′ (SEQ ID NO: 3237)5′-UGAAUAUUAUCAUGCUUUGGACUct-3′ (SEQ ID NO: 2714)3′-AUACUUAUAAUAGUACGAAACCUGAGA-5′ (SEQ ID NO: 2190) HIF-1α-1256 Target:5′-TATGAATATTATCATGCTTTGGACTCT-3′ (SEQ ID NO: 3238)5′-CUGACCAAAACUCAUCAUGAUAUgt-3′ (SEQ ID NO: 2715)3′-UAGACUGGUUUUGAGUAGUACUAUACA-5′ (SEQ ID NO: 2191) HIF-1α-1287 Target:5′-ATCTGACCAAAACTCATCATGATATGT-3′ (SEQ ID NO: 3239)5′-CAAAACUCAUCAUGAUAUGUUUAct-3′ (SEQ ID NO: 2716)3′-UGGUUUUGAGUAGUACUAUACAAAUGA-5′ (SEQ ID NO: 2192) HIF-1α-1292 Target:5′-ACCAAAACTCATCATGATATGTTTACT-3′ (SEQ ID NO: 3240)5′-AAAACUCAUCAUGAUAUGUUUACta-3′ (SEQ ID NO: 2717)3′-GGUUUUGAGUAGUACUAUACAAAUGAU-5′ (SEQ ID NO: 2193) HIF-1α-1293 Target:5′-CCAAAACTCATCATGATATGTTTACTA-3′ (SEQ ID NO: 3241)5′-CAUGAUAUGUUUACUAAAGGACAag-3′ (SEQ ID NO: 2718)3′-UAGUACUAUACAAAUGAUUUCCUGUUC-5′ (SEQ ID NO: 2194) HIF-1α-1302 Target:5′-ATCATGATATGTTTACTAAAGGACAAG-3′ (SEQ ID NO: 3242)5′-AUAUGUUUACUAAAGGACAAGUCac-3′ (SEQ ID NO: 2719)3′-ACUAUACAAAUGAUUUCCUGUUCAGUG-5′ (SEQ ID NO: 2195) HIF-1α-1306 Target:5′-TGATATGTTTACTAAAGGACAAGTCAC-3′ (SEQ ID NO: 3243)5′-GGUGGAUAUGUCUGGGUUGAAACtc-3′ (SEQ ID NO: 2720)3′-CUCCACCUAUACAGACCCAACUUUGAG-5′ (SEQ ID NO: 2196) HIF-1α-1362 Target:5′-GAGGTGGATATGTCTGGGTTGAAACTC-3′ (SEQ ID NO: 3244)5′-GGUUGAAACUCAAGCAACUGUCAta-3′ (SEQ ID NO: 2721)3′-ACCCAACUUUGAGUUCGUUGACAGUAU-5′ (SEQ ID NO: 2197) HIF-1α-1376 Target:5′-TGGGTTGAAACTCAAGCAACTGTCATA-3′ (SEQ ID NO: 3245)5′-CUGUCAUAUAUAACACCAAGAAUtc-3′ (SEQ ID NO: 2722)3′-UUGACAGUAUAUAUUGUGGUUCUUAAG-5′ (SEQ ID NO: 2198) HIF-1α-1393 Target:5′-AACTGTCATATATAACACCAAGAATTC-3′ (SEQ ID NO: 3246)5′-CAAGAAUUCUCAACCACAGUGCAtt-3′ (SEQ ID NO: 2723)3′-UGGUUCUUAAGAGUUGGUGUCACGUAA-5′ (SEQ ID NO: 2199) HIF-1α-1409 Target:5′-ACCAAGAATTCTCAACCACAGTGCATT-3′ (SEQ ID NO: 3247)5′-CAGUGCAUUGUAUGUGUGAAUUAcg-3′ (SEQ ID NO: 2724)3′-GUGUCACGUAACAUACACACUUAAUGC-5′ (SEQ ID NO: 2200) HIF-1α-1425 Target:5′-CACAGTGCATTGTATGTGTGAATTACG-3′ (SEQ ID NO: 3248)5′-AGUGCAUUGUAUGUGUGAAUUACgt-3′ (SEQ ID NO: 2725)3′-UGUCACGUAACAUACACACUUAAUGCA-5′ (SEQ ID NO: 2201) HIF-1α-1426 Target:5′-ACAGTGCATTGTATGTGTGAATTACGT-3′ (SEQ ID NO: 3249)5′-GUGUGAAUUACGUUGUGAGUGGUat-3′ (SEQ ID NO: 2726)3′-UACACACUUAAUGCAACACUCACCAUA-5′ (SEQ ID NO: 2202) HIF-1α-1438 Target:5′-ATGTGTGAATTACGTTGTGAGTGGTAT-3′ (SEQ ID NO: 3250)5′-UGUGAAUUACGUUGUGAGUGGUAtt-3′ (SEQ ID NO: 2727)3′-ACACACUUAAUGCAACACUCACCAUAA-5′ (SEQ ID NO: 2203) HIF-1α-1439 Target:5′-TGTGTGAATTACGTTGTGAGTGGTATT-3′ (SEQ ID NO: 3251)5′-GUGAAUUACGUUGUGAGUGGUAUta-3′ (SEQ ID NO: 2728)3′-CACACUUAAUGCAACACUCACCAUAAU-5′ (SEQ ID NO: 2204) HIF-1α-1440 Target:5′-GTGTGAATTACGTTGTGAGTGGTATTA-3′ (SEQ ID NO: 3252)5′-UGAAUUACGUUGUGAGUGGUAUUat-3′ (SEQ ID NO: 2729)3′-ACACUUAAUGCAACACUCACCAUAAUA-5′ (SEQ ID NO: 2205) HIF-1α-1441 Target:5′-TGTGAATTACGTTGTGAGTGGTATTAT-3′ (SEQ ID NO: 3253)5′-GUAUUAUUCAGCACGACUUGAUUtt-3′ (SEQ ID NO: 2730)3′-ACCAUAAUAAGUCGUGCUGAACUAAAA-5′ (SEQ ID NO: 2206) HIF-1α-1459 Target:5′-TGGTATTATTCAGCACGACTTGATTTT-3′ (SEQ ID NO: 3254)5′-UGAUUUUCUCCCUUCAACAAACAga-3′ (SEQ ID NO: 2731)3′-GAACUAAAAGAGGGAAGUUGUUUGUCU-5′ (SEQ ID NO: 2207) HIF-1α-1477 Target:5′-CTTGATTTTCTCCCTTCAACAAACAGA-3′ (SEQ ID NO: 3255)5′-CAAACAGAAUGUGUCCUUAAACCgg-3′ (SEQ ID NO: 2732)3′-UUGUUUGUCUUACACAGGAAUUUGGCC-5′ (SEQ ID NO: 2208) HIF-1α-1494 Target:5′-AACAAACAGAATGTGTCCTTAAACCGG-3′ (SEQ ID NO: 3256)5′-UGUGUCCUUAAACCGGUUGAAUCtt-3′ (SEQ ID NO: 2733)3′-UUACACAGGAAUUUGGCCAACUUAGAA-5′ (SEQ ID NO: 2209) HIF-1α-1503 Target:5′-AATGTGTCCTTAAACCGGTTGAATCTT-3′ (SEQ ID NO: 3257)5′-CGGUUGAAUCUUCAGAUAUGAAAat-3′ (SEQ ID NO: 2734)3′-UGGCCAACUUAGAAGUCUAUACUUUUA-5′ (SEQ ID NO: 2210) HIF-1α-1516 Target:5′-ACCGGTTGAATCTTCAGATATGAAAAT-3′ (SEQ ID NO: 3258)5′-GGUUGAAUCUUCAGAUAUGAAAAtg-3′ (SEQ ID NO: 2735)3′-GGCCAACUUAGAAGUCUAUACUUUUAC-5′ (SEQ ID NO: 2211) HIF-1α-1517 Target:5′-CCGGTTGAATCTTCAGATATGAAAATG-3′ (SEQ ID NO: 3259)5′-GUUGAAUCUUCAGAUAUGAAAAUga-3′ (SEQ ID NO: 2736)3′-GCCAACUUAGAAGUCUAUACUUUUACU-5′ (SEQ ID NO: 2212) HIF-1α-1518 Target:5′-CGGTTGAATCTTCAGATATGAAAATGA-3′ (SEQ ID NO: 3260)5′-UGAAUCUUCAGAUAUGAAAAUGAct-3′ (SEQ ID NO: 2737)3′-CAACUUAGAAGUCUAUACUUUUACUGA-5′ (SEQ ID NO: 2213) HIF-1α-1520 Target:5′-GTTGAATCTTCAGATATGAAAATGACT-3′ (SEQ ID NO: 3261)5′-GAAUCUUCAGAUAUGAAAAUGACtc-3′ (SEQ ID NO: 2738)3′-AACUUAGAAGUCUAUACUUUUACUGAG-5′ (SEQ ID NO: 2214) HIF-1α-1521 Target:5′-TTGAATCTTCAGATATGAAAATGACTC-3′ (SEQ ID NO: 3262)5′-AUAUGAAAAUGACUCAGCUAUUCac-3′ (SEQ ID NO: 2739)3′-UCUAUACUUUUACUGAGUCGAUAAGUG-5′ (SEQ ID NO: 2215) HIF-1α-1531 Target:5′-AGATATGAAAATGACTCAGCTATTCAC-3′ (SEQ ID NO: 3263)5′-UAUGAAAAUGACUCAGCUAUUCAcc-3′ (SEQ ID NO: 2740)3′-CUAUACUUUUACUGAGUCGAUAAGUGG-5′ (SEQ ID NO: 2216) HIF-1α-1532 Target:5′-GATATGAAAATGACTCAGCTATTCACC-3′ (SEQ ID NO: 3264)5′-AGUUGAAUCAGAAGAUACAAGUAgc-3′ (SEQ ID NO: 2741)3′-UUUCAACUUAGUCUUCUAUGUUCAUCG-5′ (SEQ ID NO: 2217) HIF-1α-1559 Target:5′-AAAGTTGAATCAGAAGATACAAGTAGC-3′ (SEQ ID NO: 3265)5′-UUGAAUCAGAAGAUACAAGUAGCct-3′ (SEQ ID NO: 2742)3′-UCAACUUAGUCUUCUAUGUUCAUCGGA-5′ (SEQ ID NO: 2218) HIF-1α-1561 Target:5′-AGTTGAATCAGAAGATACAAGTAGCCT-3′ (SEQ ID NO: 3266)5′-GAAGAUACAAGUAGCCUCUUUGAca-3′ (SEQ ID NO: 2743)3′-GUCUUCUAUGUUCAUCGGAGAAACUGU-5′ (SEQ ID NO: 2219) HIF-1α-1569 Target:5′-CAGAAGATACAAGTAGCCTCTTTGACA-3′ (SEQ ID NO: 3267)5′-AAGAUACAAGUAGCCUCUUUGACaa-3′ (SEQ ID NO: 2744)3′-UCUUCUAUGUUCAUCGGAGAAACUGUU-5′ (SEQ ID NO: 2220) HIF-1α-1570 Target:5′-AGAAGATACAAGTAGCCTCTTTGACAA-3′ (SEQ ID NO: 3268)5′-AGAUACAAGUAGCCUCUUUGACAaa-3′ (SEQ ID NO: 2745)3′-CUUCUAUGUUCAUCGGAGAAACUGUUU-5′ (SEQ ID NO: 2221) HIF-1α-1571 Target:5′-GAAGATACAAGTAGCCTCTTTGACAAA-3′ (SEQ ID NO: 3269)5′-CUUUGACAAACUUAAGAAGGAACct-3′ (SEQ ID NO: 2746)3′-GAGAAACUGUUUGAAUUCUUCCUUGGA-5′ (SEQ ID NO: 2222) HIF-1α-1586 Target:5′-CTCTTTGACAAACTTAAGAAGGAACCT-3′ (SEQ ID NO: 3270)5′-UUUGACAAACUUAAGAAGGAACCtg-3′ (SEQ ID NO: 2747)3′-AGAAACUGUUUGAAUUCUUCCUUGGAC-5′ (SEQ ID NO: 2223) HIF-1α-1587 Target:5′-TCTTTGACAAACTTAAGAAGGAACCTG-3′ (SEQ ID NO: 3271)5′-CUGAUGCUUUAACUUUGCUGGCCcc-3′ (SEQ ID NO: 2748)3′-UGGACUACGAAAUUGAAACGACCGGGG-5′ (SEQ ID NO: 2224) HIF-1α-1609 Target:5′-ACCTGATGCTTTAACTTTGCTGGCCCC-3′ (SEQ ID NO: 3272)5′-GGAGACACAAUCAUAUCUUUAGAtt-3′ (SEQ ID NO: 2749)3′-GACCUCUGUGUUAGUAUAGAAAUCUAA-5′ (SEQ ID NO: 2225) HIF-1α-1641 Target:5′-CTGGAGACACAATCATATCTTTAGATT-3′ (SEQ ID NO: 3273)5′-GAGACACAAUCAUAUCUUUAGAUtt-3′ (SEQ ID NO: 2750)3′-ACCUCUGUGUUAGUAUAGAAAUCUAAA-5′ (SEQ ID NO: 2226) HIF-1α-1642 Target:5′-TGGAGACACAATCATATCTTTAGATTT-3′ (SEQ ID NO: 3274)5′-CUUGAGGAAGUACCAUUAUAUAAtg-3′ (SEQ ID NO: 2751)3′-UUGAACUCCUUCAUGGUAAUAUAUUAC-5′ (SEQ ID NO: 2227) HIF-1α-1701 Target:5′-AACTTGAGGAAGTACCATTATATAATG-3′ (SEQ ID NO: 3275)5′-UUGAGGAAGUACCAUUAUAUAAUga-3′ (SEQ ID NO: 2752)3′-UGAACUCCUUCAUGGUAAUAUAUUACU-5′ (SEQ ID NO: 2228) HIF-1α-1702 Target:5′-ACTTGAGGAAGTACCATTATATAATGA-3′ (SEQ ID NO: 3276)5′-GAGGAAGUACCAUUAUAUAAUGAtg-3′ (SEQ ID NO: 2753)3′-AACUCCUUCAUGGUAAUAUAUUACUAC-5′ (SEQ ID NO: 2229) HIF-1α-1704 Target:5′-TTGAGGAAGTACCATTATATAATGATG-3′ (SEQ ID NO: 3277)5′-AGGAAGUACCAUUAUAUAAUGAUgt-3′ (SEQ ID NO: 2754)3′-ACUCCUUCAUGGUAAUAUAUUACUACA-5′ (SEQ ID NO: 2230) HIF-1α-1705 Target:5′-TGAGGAAGTACCATTATATAATGATGT-3′ (SEQ ID NO: 3278)5′-GAAGUACCAUUAUAUAAUGAUGUaa-3′ (SEQ ID NO: 2755)3′-UCCUUCAUGGUAAUAUAUUACUACAUU-5′ (SEQ ID NO: 2231) HIF-1α-1707 Target:5′-AGGAAGTACCATTATATAATGATGTAA-3′ (SEQ ID NO: 3279)5′-AAGUACCAUUAUAUAAUGAUGUAat-3′ (SEQ ID NO: 2756)3′-CCUUCAUGGUAAUAUAUUACUACAUUA-5′ (SEQ ID NO: 2232) HIF-1α-1708 Target:5′-GGAAGTACCATTATATAATGATGTAAT-3′ (SEQ ID NO: 3280)5′-CGAAAAAUUACAGAAUAUAAAUUtg-3′ (SEQ ID NO: 2757)3′-UUGCUUUUUAAUGUCUUAUAUUUAAAC-5′ (SEQ ID NO: 2233) HIF-1α-1748 Target:5′-AACGAAAAATTACAGAATATAAATTTG-3′ (SEQ ID NO: 3281)5′-GAAAAAUUACAGAAUAUAAAUUUgg-3′ (SEQ ID NO: 2758)3′-UGCUUUUUAAUGUCUUAUAUUUAAACC-5′ (SEQ ID NO: 2234) HIF-1α-1749 Target:5′-ACGAAAAATTACAGAATATAAATTTGG-3′ (SEQ ID NO: 3282)5′-AAAUUACAGAAUAUAAAUUUGGCaa-3′ (SEQ ID NO: 2759)3′-UUUUUAAUGUCUUAUAUUUAAACCGUU-5′ (SEQ ID NO: 2235) HIF-1α-1752 Target:5′-AAAAATTACAGAATATAAATTTGGCAA-3′ (SEQ ID NO: 3283)5′-CAGAAUAUAAAUUUGGCAAUGUCtc-3′ (SEQ ID NO: 2760)3′-AUGUCUUAUAUUUAAACCGUUACAGAG-5′ (SEQ ID NO: 2236) HIF-1α-1758 Target:5′-TACAGAATATAAATTTGGCAATGTCTC-3′ (SEQ ID NO: 3284)5′-AGAAUAUAAAUUUGGCAAUGUCUcc-3′ (SEQ ID NO: 2761)3′-UGUCUUAUAUUUAAACCGUUACAGAGG-5′ (SEQ ID NO: 2237) HIF-1α-1759 Target:5′-ACAGAATATAAATTTGGCAATGTCTCC-3′ (SEQ ID NO: 3285)5′-CAAGAAGUUGCAUUAAAAUUAGAac-3′ (SEQ ID NO: 2762)3′-UAGUUCUUCAACGUAAUUUUAAUCUUG-5′ (SEQ ID NO: 2238) HIF-1α-1842 Target:5′-ATCAAGAAGTTGCATTAAAATTAGAAC-3′ (SEQ ID NO: 3286)5′-AAGAAGUUGCAUUAAAAUUAGAAcc-3′ (SEQ ID NO: 2763)3′-AGUUCUUCAACGUAAUUUUAAUCUUGG-5′ (SEQ ID NO: 2239) HIF-1α-1843 Target:5′-TCAAGAAGTTGCATTAAAATTAGAACC-3′ (SEQ ID NO: 3287)5′-AAAUUAGAACCAAAUCCAGAGUCac-3′ (SEQ ID NO: 2764)3′-AUUUUAAUCUUGGUUUAGGUCUCAGUG-5′ (SEQ ID NO: 2240) HIF-1α-1857 Target:5′-TAAAATTAGAACCAAATCCAGAGTCAC-3′ (SEQ ID NO: 3288)5′-AAUUAGAACCAAAUCCAGAGUCAct-3′ (SEQ ID NO: 2765)3′-UUUUAAUCUUGGUUUAGGUCUCAGUGA-5′ (SEQ ID NO: 2241) HIF-1α-1858 Target:5′-AAAATTAGAACCAAATCCAGAGTCACT-3′ (SEQ ID NO: 3289)5′-AGAGUCACUGGAACUUUCUUUUAcc-3′ (SEQ ID NO: 2766)3′-GGUCUCAGUGACCUUGAAAGAAAAUGG-5′ (SEQ ID NO: 2242) HIF-1α-1874 Target:5′-CCAGAGTCACTGGAACTTTCTTTTACC-3′ (SEQ ID NO: 3290)5′-GAGUCACUGGAACUUUCUUUUACca-3′ (SEQ ID NO: 2767)3′-GUCUCAGUGACCUUGAAAGAAAAUGGU-5′ (SEQ ID NO: 2243) HIF-1α-1875 Target:5′-CAGAGTCACTGGAACTTTCTTTTACCA-3′ (SEQ ID NO: 3291)5′-CUGGAACUUUCUUUUACCAUGCCcc-3′ (SEQ ID NO: 2768)3′-GUGACCUUGAAAGAAAAUGGUACGGGG-5′ (SEQ ID NO: 2244) HIF-1α-1881 Target:5′-CACTGGAACTTTCTTTTACCATGCCCC-3′ (SEQ ID NO: 3292)5′-CUAAUAGUCCCAGUGAAUAUUGUtt-3′ (SEQ ID NO: 2769)3′-CGGAUUAUCAGGGUCACUUAUAACAAA-5′ (SEQ ID NO: 2245) HIF-1α-1966 Target:5′-GCCTAATAGTCCCAGTGAATATTGTTT-3′ (SEQ ID NO: 3293)5′-UAAUAGUCCCAGUGAAUAUUGUUtt-3′ (SEQ ID NO: 2770)3′-GGAUUAUCAGGGUCACUUAUAACAAAA-5′ (SEQ ID NO: 2246) HIF-1α-1967 Target:5′-CCTAATAGTCCCAGTGAATATTGTTTT-3′ (SEQ ID NO: 3294)5′-AAUAGUCCCAGUGAAUAUUGUUUtt-3′ (SEQ ID NO: 2771)3′-GAUUAUCAGGGUCACUUAUAACAAAAA-5′ (SEQ ID NO: 2247) HIF-1α-1968 Target:5′-CTAATAGTCCCAGTGAATATTGTTTTT-3′ (SEQ ID NO: 3295)5′-AUAGUCCCAGUGAAUAUUGUUUUta-3′ (SEQ ID NO: 2772)3′-AUUAUCAGGGUCACUUAUAACAAAAAU-5′ (SEQ ID NO: 2248) HIF-1α-1969 Target:5′-TAATAGTCCCAGTGAATATTGTTTTTA-3′ (SEQ ID NO: 3296)5′-UAGUCCCAGUGAAUAUUGUUUUUat-3′ (SEQ ID NO: 2773)3′-UUAUCAGGGUCACUUAUAACAAAAAUA-5′ (SEQ ID NO: 2249) HIF-1α-1970 Target:5′-AATAGTCCCAGTGAATATTGTTTTTAT-3′ (SEQ ID NO: 3297)5′-GUGAAUAUUGUUUUUAUGUGGAUag-3′ (SEQ ID NO: 2774)3′-GUCACUUAUAACAAAAAUACACCUAUC-5′ (SEQ ID NO: 2250) HIF-1α-1978 Target:5′-CAGTGAATATTGTTTTTATGTGGATAG-3′ (SEQ ID NO: 3298)5′-UGAAUAUUGUUUUUAUGUGGAUAgt-3′ (SEQ ID NO: 2775)3′-UCACUUAUAACAAAAAUACACCUAUCA-5′ (SEQ ID NO: 2251) HIF-1α-1979 Target:5′-AGTGAATATTGTTTTTATGTGGATAGT-3′ (SEQ ID NO: 3299)5′-AAUAUUGUUUUUAUGUGGAUAGUga-3′ (SEQ ID NO: 2776)3′-ACUUAUAACAAAAAUACACCUAUCACU-5′ (SEQ ID NO: 2252) HIF-1α-1981 Target:5′-TGAATATTGTTTTTATGTGGATAGTGA-3′ (SEQ ID NO: 3300)5′-UAUUGUUUUUAUGUGGAUAGUGAta-3′ (SEQ ID NO: 2777)3′-UUAUAACAAAAAUACACCUAUCACUAU-5′ (SEQ ID NO: 2253) HIF-1α-1983 Target:5′-AATATTGTTTTTATGTGGATAGTGATA-3′ (SEQ ID NO: 3301)5′-AUUGUUUUUAUGUGGAUAGUGAUat-3′ (SEQ ID NO: 2778)3′-UAUAACAAAAAUACACCUAUCACUAUA-5′ (SEQ ID NO: 2254) HIF-1α-1984 Target:5′-ATATTGTTTTTATGTGGATAGTGATAT-3′ (SEQ ID NO: 3302)5′-UGUUUUUAUGUGGAUAGUGAUAUgg-3′ (SEQ ID NO: 2779)3′-UAACAAAAAUACACCUAUCACUAUACC-5′ (SEQ ID NO: 2255) HIF-1α-1986 Target:5′-ATTGTTTTTATGTGGATAGTGATATGG-3′ (SEQ ID NO: 3303)5′-UUUUAUGUGGAUAGUGAUAUGGUca-3′ (SEQ ID NO: 2780)3′-CAAAAAUACACCUAUCACUAUACCAGU-5′ (SEQ ID NO: 2256) HIF-1α-1989 Target:5′-GTTTTTATGTGGATAGTGATATGGTCA-3′ (SEQ ID NO: 3304)5′-UGGAUAGUGAUAUGGUCAAUGAAtt-3′ (SEQ ID NO: 2781)3′-ACACCUAUCACUAUACCAGUUACUUAA-5′ (SEQ ID NO: 2257) HIF-1α-1996 Target:5′-TGTGGATAGTGATATGGTCAATGAATT-3′ (SEQ ID NO: 3305)5′-GAUAGUGAUAUGGUCAAUGAAUUca-3′ (SEQ ID NO: 2782)3′-ACCUAUCACUAUACCAGUUACUUAAGU-5′ (SEQ ID NO: 2258) HIF-1α-1998 Target:5′-TGGATAGTGATATGGTCAATGAATTCA-3′ (SEQ ID NO: 3306)5′-AUAGUGAUAUGGUCAAUGAAUUCaa-3′ (SEQ ID NO: 2783)3′-CCUAUCACUAUACCAGUUACUUAAGUU-5′ (SEQ ID NO: 2259) HIF-1α-1999 Target:5′-GGATAGTGATATGGTCAATGAATTCAA-3′ (SEQ ID NO: 3307)5′-UAGUGAUAUGGUCAAUGAAUUCAag-3′ (SEQ ID NO: 2784)3′-CUAUCACUAUACCAGUUACUUAAGUUC-5′ (SEQ ID NO: 2260) HIF-1α-2000 Target:5′-GATAGTGATATGGTCAATGAATTCAAG-3′ (SEQ ID NO: 3308)5′-GAUAUGGUCAAUGAAUUCAAGUUgg-3′ (SEQ ID NO: 2785)3′-CACUAUACCAGUUACUUAAGUUCAACC-5′ (SEQ ID NO: 2261) HIF-1α-2004 Target:5′-GTGATATGGTCAATGAATTCAAGTTGG-3′ (SEQ ID NO: 3309)5′-AUGGUCAAUGAAUUCAAGUUGGAat-3′ (SEQ ID NO: 2786)3′-UAUACCAGUUACUUAAGUUCAACCUUA-5′ (SEQ ID NO: 2262) HIF-1α-2007 Target:5′-ATATGGTCAATGAATTCAAGTTGGAAT-3′ (SEQ ID NO: 3310)5′-UGGUCAAUGAAUUCAAGUUGGAAtt-3′ (SEQ ID NO: 2787)3′-AUACCAGUUACUUAAGUUCAACCUUAA-5′ (SEQ ID NO: 2263) HIF-1α-2008 Target:5′-TATGGTCAATGAATTCAAGTTGGAATT-3′ (SEQ ID NO: 3311)5′-AAUGAAUUCAAGUUGGAAUUGGUag-3′ (SEQ ID NO: 2788)3′-AGUUACUUAAGUUCAACCUUAACCAUC-5′ (SEQ ID NO: 2264) HIF-1α-2013 Target:5′-TCAATGAATTCAAGTTGGAATTGGTAG-3′ (SEQ ID NO: 3312)5′-AUGAAUUCAAGUUGGAAUUGGUAga-3′ (SEQ ID NO: 2789)3′-GUUACUUAAGUUCAACCUUAACCAUCU-5′ (SEQ ID NO: 2265) HIF-1α-2014 Target:5′-CAATGAATTCAAGTTGGAATTGGTAGA-3′ (SEQ ID NO: 3313)5′-GAAUUCAAGUUGGAAUUGGUAGAaa-3′ (SEQ ID NO: 2790)3′-UACUUAAGUUCAACCUUAACCAUCUUU-5′ (SEQ ID NO: 2266) HIF-1α-2016 Target:5′-ATGAATTCAAGTTGGAATTGGTAGAAA-3′ (SEQ ID NO: 3314)5′-AAGUUGGAAUUGGUAGAAAAACUtt-3′ (SEQ ID NO: 2791)3′-AGUUCAACCUUAACCAUCUUUUUGAAA-5′ (SEQ ID NO: 2267) HIF-1α-2022 Target:5′-TCAAGTTGGAATTGGTAGAAAAACTTT-3′ (SEQ ID NO: 3315)5′-GAAUUGGUAGAAAAACUUUUUGCtg-3′ (SEQ ID NO: 2792)3′-ACCUUAACCAUCUUUUUGAAAAACGAC-5′ (SEQ ID NO: 2268) HIF-1α-2028 Target:5′-TGGAATTGGTAGAAAAACTTTTTGCTG-3′ (SEQ ID NO: 3316)5′-AAUUGGUAGAAAAACUUUUUGCUga-3′ (SEQ ID NO: 2793)3′-CCUUAACCAUCUUUUUGAAAAACGACU-5′ (SEQ ID NO: 2269) HIF-1α-2029 Target:5′-GGAATTGGTAGAAAAACTTTTTGCTGA-3′ (SEQ ID NO: 3317)5′-UAGAAAAACUUUUUGCUGAAGACac-3′ (SEQ ID NO: 2794)3′-CCAUCUUUUUGAAAAACGACUUCUGUG-5′ (SEQ ID NO: 2270) HIF-1α-2035 Target:5′-GGTAGAAAAACTTTTTGCTGAAGACAC-3′ (SEQ ID NO: 3318)5′-AGAAAAACUUUUUGCUGAAGACAca-3′ (SEQ ID NO: 2795)3′-CAUCUUUUUGAAAAACGACUUCUGUGU-5′ (SEQ ID NO: 2271) HIF-1α-2036 Target:5′-GTAGAAAAACTTTTTGCTGAAGACACA-3′ (SEQ ID NO: 3319)5′-CUUUUUGCUGAAGACACAGAAGCaa-3′ (SEQ ID NO: 2796)3′-UUGAAAAACGACUUCUGUGUCUUCGUU-5′ (SEQ ID NO: 2272) HIF-1α-2043 Target:5′-AACTTTTTGCTGAAGACACAGAAGCAA-3′ (SEQ ID NO: 3320)5′-CUGAAGACACAGAAGCAAAGAACcc-3′ (SEQ ID NO: 2797)3′-ACGACUUCUGUGUCUUCGUUUCUUGGG-5′ (SEQ ID NO: 2273) HIF-1α-2050 Target:5′-TGCTGAAGACACAGAAGCAAAGAACCC-3′ (SEQ ID NO: 3321)5′-UGAAGACACAGAAGCAAAGAACCca-3′ (SEQ ID NO: 2798)3′-CGACUUCUGUGUCUUCGUUUCUUGGGU-5′ (SEQ ID NO: 2274) HIF-1α-2051 Target:5′-GCTGAAGACACAGAAGCAAAGAACCCA-3′ (SEQ ID NO: 3322)5′-CAGAAGCAAAGAACCCAUUUUCUac-3′ (SEQ ID NO: 2799)3′-GUGUCUUCGUUUCUUGGGUAAAAGAUG-5′ (SEQ ID NO: 2275) HIF-1α-2059 Target:5′-CACAGAAGCAAAGAACCCATTTTCTAC-3′ (SEQ ID NO: 3323)5′-AGAACCCAUUUUCUACUCAGGACac-3′ (SEQ ID NO: 2800)3′-UUUCUUGGGUAAAAGAUGAGUCCUGUG-5′ (SEQ ID NO: 2276) HIF-1α-2068 Target:5′-AAAGAACCCATTTTCTACTCAGGACAC-3′ (SEQ ID NO: 3324)5′-CAGGACACAGAUUUAGACUUGGAga-3′ (SEQ ID NO: 2801)3′-GAGUCCUGUGUCUAAAUCUGAACCUCU-5′ (SEQ ID NO: 2277) HIF-1α-2085 Target:5′-CTCAGGACACAGATTTAGACTTGGAGA-3′ (SEQ ID NO: 3325)5′-CAGAUUUAGACUUGGAGAUGUUAgc-3′ (SEQ ID NO: 2802)3′-GUGUCUAAAUCUGAACCUCUACAAUCG-5′ (SEQ ID NO: 2278) HIF-1α-2092 Target:5′-CACAGATTTAGACTTGGAGATGTTAGC-3′ (SEQ ID NO: 3326)5′-GAUUUAGACUUGGAGAUGUUAGCtc-3′ (SEQ ID NO: 2803)3′-GUCUAAAUCUGAACCUCUACAAUCGAG-5′ (SEQ ID NO: 2279) HIF-1α-2094 Target:5′-CAGATTTAGACTTGGAGATGTTAGCTC-3′ (SEQ ID NO: 3327)5′-AUUUAGACUUGGAGAUGUUAGCUcc-3′ (SEQ ID NO: 2804)3′-UCUAAAUCUGAACCUCUACAAUCGAGG-5′ (SEQ ID NO: 2280) HIF-1α-2095 Target:5′-AGATTTAGACTTGGAGATGTTAGCTCC-3′ (SEQ ID NO: 3328)5′-GGAGAUGUUAGCUCCCUAUAUCCca-3′ (SEQ ID NO: 2805)3′-AACCUCUACAAUCGAGGGAUAUAGGGU-5′ (SEQ ID NO: 2281) HIF-1α-2105 Target:5′-TTGGAGATGTTAGCTCCCTATATCCCA-3′ (SEQ ID NO: 3329)5′-AUGAUGACUUCCAGUUACGUUCCtt-3′ (SEQ ID NO: 2806)3′-CCUACUACUGAAGGUCAAUGCAAGGAA-5′ (SEQ ID NO: 2282) HIF-1α-2134 Target:5′-GGATGATGACTTCCAGTTACGTTCCTT-3′ (SEQ ID NO: 3330)5′-CGAUCAGUUGUCACCAUUAGAAAgc-3′ (SEQ ID NO: 2807)3′-AAGCUAGUCAACAGUGGUAAUCUUUCG-5′ (SEQ ID NO: 2283) HIF-1α-2159 Target:5′-TTCGATCAGTTGTCACCATTAGAAAGC-3′ (SEQ ID NO: 3331)5′-UUGUCACCAUUAGAAAGCAGUUCcg-3′ (SEQ ID NO: 2808)3′-UCAACAGUGGUAAUCUUUCGUCAAGGC-5′ (SEQ ID NO: 2284) HIF-1α-2166 Target:5′-AGTTGTCACCATTAGAAAGCAGTTCCG-3′ (SEQ ID NO: 3332)5′-CAGUUACAGUAUUCCAGCAGACUca-3′ (SEQ ID NO: 2809)3′-GUGUCAAUGUCAUAAGGUCGUCUGAGU-5′ (SEQ ID NO: 2285) HIF-1α-2221 Target:5′-CACAGTTACAGTATTCCAGCAGACTCA-3′ (SEQ ID NO: 3333)5′-GAAUUAAAAACAGUGACAAAAGAcc-3′ (SEQ ID NO: 2810)3′-UACUUAAUUUUUGUCACUGUUUUCUGG-5′ (SEQ ID NO: 2286) HIF-1α-2295 Target:5′-ATGAATTAAAAACAGTGACAAAAGACC-3′ (SEQ ID NO: 3334)5′-AAUUAAAAACAGUGACAAAAGACcg-3′ (SEQ ID NO: 2811)3′-ACUUAAUUUUUGUCACUGUUUUCUGGC-5′ (SEQ ID NO: 2287) HIF-1α-2296 Target:5′-TGAATTAAAAACAGTGACAAAAGACCG-3′ (SEQ ID NO: 3335)5′-AUUAAAAACAGUGACAAAAGACCgt-3′ (SEQ ID NO: 2812)3′-CUUAAUUUUUGUCACUGUUUUCUGGCA-5′ (SEQ ID NO: 2288) HIF-1α-2297 Target:5′-GAATTAAAAACAGTGACAAAAGACCGT-3′ (SEQ ID NO: 3336)5′-CAGUGACAAAAGACCGUAUGGAAga-3′ (SEQ ID NO: 2813)3′-UUGUCACUGUUUUCUGGCAUACCUUCU-5′ (SEQ ID NO: 2289) HIF-1α-2305 Target:5′-AACAGTGACAAAAGACCGTATGGAAGA-3′ (SEQ ID NO: 3337)5′-GUGACAAAAGACCGUAUGGAAGAca-3′ (SEQ ID NO: 2814)3′-GUCACUGUUUUCUGGCAUACCUUCUGU-5′ (SEQ ID NO: 2290) HIF-1α-2307 Target:5′-CAGTGACAAAAGACCGTATGGAAGACA-3′ (SEQ ID NO: 3338)5′-CGUAUGGAAGACAUUAAAAUAUUga-3′ (SEQ ID NO: 2815)3′-UGGCAUACCUUCUGUAAUUUUAUAACU-5′ (SEQ ID NO: 2291) HIF-1α-2319 Target:5′-ACCGTATGGAAGACATTAAAATATTGA-3′ (SEQ ID NO: 3339)5′-AUGGAAGACAUUAAAAUAUUGAUtg-3′ (SEQ ID NO: 2816)3′-CAUACCUUCUGUAAUUUUAUAACUAAC-5′ (SEQ ID NO: 2292) HIF-1α-2322 Target:5′-GTATGGAAGACATTAAAATATTGATTG-3′ (SEQ ID NO: 3340)5′-UGGAAGACAUUAAAAUAUUGAUUgc-3′ (SEQ ID NO: 2817)3′-AUACCUUCUGUAAUUUUAUAACUAACG-5′ (SEQ ID NO: 2293) HIF-1α-2323 Target:5′-TATGGAAGACATTAAAATATTGATTGC-3′ (SEQ ID NO: 3341)5′-GAAGACAUUAAAAUAUUGAUUGCat-3′ (SEQ ID NO: 2818)3′-ACCUUCUGUAAUUUUAUAACUAACGUA-5′ (SEQ ID NO: 2294) HIF-1α-2325 Target:5′-TGGAAGACATTAAAATATTGATTGCAT-3′ (SEQ ID NO: 3342)5′-AUAGAGAUACUCAAAGUCGGACAgc-3′ (SEQ ID NO: 2819)3′-UAUAUCUCUAUGAGUUUCAGCCUGUCG-5′ (SEQ ID NO: 2295) HIF-1α-2404 Target:5′-ATATAGAGATACTCAAAGTCGGACAGC-3′ (SEQ ID NO: 3343)5′-GAAAAGGAGUCAUAGAACAGACAga-3′ (SEQ ID NO: 2820)3′-UCCUUUUCCUCAGUAUCUUGUCUGUCU-5′ (SEQ ID NO: 2296) HIF-1α-2446 Target:5′-AGGAAAAGGAGTCATAGAACAGACAGA-3′ (SEQ ID NO: 3344)5′-AGGAGUCAUAGAACAGACAGAAAaa-3′ (SEQ ID NO: 2821)3′-UUUCCUCAGUAUCUUGUCUGUCUUUUU-5′ (SEQ ID NO: 2297) HIF-1α-2450 Target:5′-AAAGGAGTCATAGAACAGACAGAAAAA-3′ (SEQ ID NO: 3345)5′-GGAGUCAUAGAACAGACAGAAAAat-3′ (SEQ ID NO: 2822)3′-UUCCUCAGUAUCUUGUCUGUCUUUUUA-5′ (SEQ ID NO: 2298) HIF-1α-2451 Target:5′-AAGGAGTCATAGAACAGACAGAAAAAT-3′ (SEQ ID NO: 3346)5′-CAGAAAAAUCUCAUCCAAGAAGCcc-3′ (SEQ ID NO: 2823)3′-CUGUCUUUUUAGAGUAGGUUCUUCGGG-5′ (SEQ ID NO: 2299) HIF-1α-2467 Target:5′-GACAGAAAAATCTCATCCAAGAAGCCC-3′ (SEQ ID NO: 3347)5′-AGAAAAAUCUCAUCCAAGAAGCCct-3′ (SEQ ID NO: 2824)3′-UGUCUUUUUAGAGUAGGUUCUUCGGGA-5′ (SEQ ID NO: 2300) HIF-1α-2468 Target:5′-ACAGAAAAATCTCATCCAAGAAGCCCT-3′ (SEQ ID NO: 3348)5′-CGUGUUAUCUGUCGCUUUGAGUCaa-3′ (SEQ ID NO: 2825)3′-UUGCACAAUAGACAGCGAAACUCAGUU-5′ (SEQ ID NO: 2301) HIF-1α-2495 Target:5′-AACGTGTTATCTGTCGCTTTGAGTCAA-3′ (SEQ ID NO: 3349)5′-GUGUUAUCUGUCGCUUUGAGUCAaa-3′ (SEQ ID NO: 2826)3′-UGCACAAUAGACAGCGAAACUCAGUUU-5′ (SEQ ID NO: 2302) HIF-1α-2496 Target:5′-ACGTGTTATCTGTCGCTTTGAGTCAAA-3′ (SEQ ID NO: 3350)5′-CUGUCGCUUUGAGUCAAAGAACUac-3′ (SEQ ID NO: 2827)3′-UAGACAGCGAAACUCAGUUUCUUGAUG-5′ (SEQ ID NO: 2303) HIF-1α-2503 Target:5′-ATCTGTCGCTTTGAGTCAAAGAACTAC-3′ (SEQ ID NO: 3351)5′-UUUGAGUCAAAGAACUACAGUUCct-3′ (SEQ ID NO: 2828)3′-CGAAACUCAGUUUCUUGAUGUCAAGGA-5′ (SEQ ID NO: 2304) HIF-1α-2510 Target:5′-GCTTTGAGTCAAAGAACTACAGTTCCT-3′ (SEQ ID NO: 3352)5′-UUGAGUCAAAGAACUACAGUUCCtg-3′ (SEQ ID NO: 2829)3′-GAAACUCAGUUUCUUGAUGUCAAGGAC-5′ (SEQ ID NO: 2305) HIF-1α-2511 Target:5′-CTTTGAGTCAAAGAACTACAGTTCCTG-3′ (SEQ ID NO: 3353)5′-CAAAGAACUACAGUUCCUGAGGAag-3′ (SEQ ID NO: 2830)3′-CAGUUUCUUGAUGUCAAGGACUCCUUC-5′ (SEQ ID NO: 2306) HIF-1α-2517 Target:5′-GTCAAAGAACTACAGTTCCTGAGGAAG-3′ (SEQ ID NO: 3354)5′-AAAGAACUACAGUUCCUGAGGAAga-3′ (SEQ ID NO: 2831)3′-AGUUUCUUGAUGUCAAGGACUCCUUCU-5′ (SEQ ID NO: 2307) HIF-1α-2518 Target:5′-TCAAAGAACTACAGTTCCTGAGGAAGA-3′ (SEQ ID NO: 3355)5′-GAGGAAGAACUAAAUCCAAAGAUac-3′ (SEQ ID NO: 2832)3′-GACUCCUUCUUGAUUUAGGUUUCUAUG-5′ (SEQ ID NO: 2308) HIF-1α-2535 Target:5′-CTGAGGAAGAACTAAATCCAAAGATAC-3′ (SEQ ID NO: 3356)5′-AGGAAGAACUAAAUCCAAAGAUAct-3′ (SEQ ID NO: 2833)3′-ACUCCUUCUUGAUUUAGGUUUCUAUGA-5′ (SEQ ID NO: 2309) HIF-1α-2536 Target:5′-TGAGGAAGAACTAAATCCAAAGATACT-3′ (SEQ ID NO: 3357)5′-GGAAGAACUAAAUCCAAAGAUACta-3′ (SEQ ID NO: 2834)3′-CUCCUUCUUGAUUUAGGUUUCUAUGAU-5′ (SEQ ID NO: 2310) HIF-1α-2537 Target:5′-GAGGAAGAACTAAATCCAAAGATACTA-3′ (SEQ ID NO: 3358)5′-GAAGAACUAAAUCCAAAGAUACUag-3′ (SEQ ID NO: 2835)3′-UCCUUCUUGAUUUAGGUUUCUAUGAUC-5′ (SEQ ID NO: 2311) HIF-1α-2538 Target:5′-AGGAAGAACTAAATCCAAAGATACTAG-3′ (SEQ ID NO: 3359)5′-AAAUCCAAAGAUACUAGCUUUGCag-3′ (SEQ ID NO: 2836)3′-GAUUUAGGUUUCUAUGAUCGAAACGUC-5′ (SEQ ID NO: 2312) HIF-1α-2546 Target:5′-CTAAATCCAAAGATACTAGCTTTGCAG-3′ (SEQ ID NO: 3360)5′-CAAAGAUACUAGCUUUGCAGAAUgc-3′ (SEQ ID NO: 2837)3′-AGGUUUCUAUGAUCGAAACGUCUUACG-5′ (SEQ ID NO: 2313) HIF-1α-2551 Target:5′-TCCAAAGATACTAGCTTTGCAGAATGC-3′ (SEQ ID NO: 3361)5′-AAGAUACUAGCUUUGCAGAAUGCtc-3′ (SEQ ID NO: 2838)3′-GUUUCUAUGAUCGAAACGUCUUACGAG-5′ (SEQ ID NO: 2314) HIF-1α-2553 Target:5′-CAAAGATACTAGCTTTGCAGAATGCTC-3′ (SEQ ID NO: 3362)5′-AGAUACUAGCUUUGCAGAAUGCUca-3′ (SEQ ID NO: 2839)3′-UUUCUAUGAUCGAAACGUCUUACGAGU-5′ (SEQ ID NO: 2315) HIF-1α-2554 Target:5′-AAAGATACTAGCTTTGCAGAATGCTCA-3′ (SEQ ID NO: 3363)5′-GAAAGCGAAAAAUGGAACAUGAUgg-3′ (SEQ ID NO: 2840)3′-CUCUUUCGCUUUUUACCUUGUACUACC-5′ (SEQ ID NO: 2316) HIF-1α-2581 Target:5′-GAGAAAGCGAAAAATGGAACATGATGG-3′ (SEQ ID NO: 3364)5′-UGGAACAUGAUGGUUCACUUUUUca-3′ (SEQ ID NO: 2841)3′-UUACCUUGUACUACCAAGUGAAAAAGU-5′ (SEQ ID NO: 2317) HIF-1α-2593 Target:5′-AATGGAACATGATGGTTCACTTTTTCA-3′ (SEQ ID NO: 3365)5′-AUGAUGGUUCACUUUUUCAAGCAgt-3′ (SEQ ID NO: 2842)3′-UGUACUACCAAGUGAAAAAGUUCGUCA-5′ (SEQ ID NO: 2318) HIF-1α-2599 Target:5′-ACATGATGGTTCACTTTTTCAAGCAGT-3′ (SEQ ID NO: 3366)5′-UUUUUCAAGCAGUAGGAAUUGGAac-3′ (SEQ ID NO: 2843)3′-UGAAAAAGUUCGUCAUCCUUAACCUUG-5′ (SEQ ID NO: 2319) HIF-1α-2611 Target:5′-ACTTTTTCAAGCAGTAGGAATTGGAAC-3′ (SEQ ID NO: 3367)5′-CAGUAGGAAUUGGAACAUUAUUAca-3′ (SEQ ID NO: 2844)3′-UCGUCAUCCUUAACCUUGUAAUAAUGU-5′ (SEQ ID NO: 2320) HIF-1α-2620 Target:5′-AGCAGTAGGAATTGGAACATTATTACA-3′ (SEQ ID NO: 3368)5′-AGUAGGAAUUGGAACAUUAUUACag-3′ (SEQ ID NO: 2845)3′-CGUCAUCCUUAACCUUGUAAUAAUGUC-5′ (SEQ ID NO: 2321) HIF-1α-2621 Target:5′-GCAGTAGGAATTGGAACATTATTACAG-3′ (SEQ ID NO: 3369)5′-GUAGGAAUUGGAACAUUAUUACAgc-3′ (SEQ ID NO: 2846)3′-GUCAUCCUUAACCUUGUAAUAAUGUCG-5′ (SEQ ID NO: 2322) HIF-1α-2622 Target:5′-CAGTAGGAATTGGAACATTATTACAGC-3′ (SEQ ID NO: 3370)5′-CUUGGAAACGUGUAAAAGGAUGCaa-3′ (SEQ ID NO: 2847)3′-AAGAACCUUUGCACAUUUUCCUACGUU-5′ (SEQ ID NO: 2323) HIF-1α-2680 Target:5′-TTCTTGGAAACGTGTAAAAGGATGCAA-3′ (SEQ ID NO: 3371)5′-UUGGAAACGUGUAAAAGGAUGCAaa-3′ (SEQ ID NO: 2848)3′-AGAACCUUUGCACAUUUUCCUACGUUU-5′ (SEQ ID NO: 2324) HIF-1α-2681 Target:5′-TCTTGGAAACGTGTAAAAGGATGCAAA-3′ (SEQ ID NO: 3372)5′-UAAAAGGAUGCAAAUCUAGUGAAca-3′ (SEQ ID NO: 2849)3′-ACAUUUUCCUACGUUUAGAUCACUUGU-5′ (SEQ ID NO: 2325) HIF-1α-2692 Target:5′-TGTAAAAGGATGCAAATCTAGTGAACA-3′ (SEQ ID NO: 3373)5′-AAAAGGAUGCAAAUCUAGUGAACag-3′ (SEQ ID NO: 2850)3′-CAUUUUCCUACGUUUAGAUCACUUGUC-5′ (SEQ ID NO: 2326) HIF-1α-2693 Target:5′-GTAAAAGGATGCAAATCTAGTGAACAG-3′ (SEQ ID NO: 3374)5′-GAUGCAAAUCUAGUGAACAGAAUgg-3′ (SEQ ID NO: 2851)3′-UCCUACGUUUAGAUCACUUGUCUUACC-5′ (SEQ ID NO: 2327) HIF-1α-2698 Target:5′-AGGATGCAAATCTAGTGAACAGAATGG-3′ (SEQ ID NO: 3375)5′-CAAAUCUAGUGAACAGAAUGGAAtg-3′ (SEQ ID NO: 2852)3′-ACGUUUAGAUCACUUGUCUUACCUUAC-5′ (SEQ ID NO: 2328) HIF-1α-2702 Target:5′-TGCAAATCTAGTGAACAGAATGGAATG-3′ (SEQ ID NO: 3376)5′-UAGUGAACAGAAUGGAAUGGAGCaa-3′ (SEQ ID NO: 2853)3′-AGAUCACUUGUCUUACCUUACCUCGUU-5′ (SEQ ID NO: 2329) HIF-1α-2708 Target:5′-TCTAGTGAACAGAATGGAATGGAGCAA-3′ (SEQ ID NO: 3377)5′-AGUGAACAGAAUGGAAUGGAGCAaa-3′ (SEQ ID NO: 2854)3′-GAUCACUUGUCUUACCUUACCUCGUUU-5′ (SEQ ID NO: 2330) HIF-1α-2709 Target:5′-CTAGTGAACAGAATGGAATGGAGCAAA-3′ (SEQ ID NO: 3378)5′-AGAAUGGAAUGGAGCAAAAGACAat-3′ (SEQ ID NO: 2855)3′-UGUCUUACCUUACCUCGUUUUCUGUUA-5′ (SEQ ID NO: 2331) HIF-1α-2716 Target:5′-ACAGAATGGAATGGAGCAAAAGACAAT-3′ (SEQ ID NO: 3379)5′-GGAAUGGAGCAAAAGACAAUUAUtt-3′ (SEQ ID NO: 2856)3′-UACCUUACCUCGUUUUCUGUUAAUAAA-5′ (SEQ ID NO: 2332) HIF-1α-2721 Target:5′-ATGGAATGGAGCAAAAGACAATTATTT-3′ (SEQ ID NO: 3380)5′-AAUGGAGCAAAAGACAAUUAUUUta-3′ (SEQ ID NO: 2857)3′-CCUUACCUCGUUUUCUGUUAAUAAAAU-5′ (SEQ ID NO: 2333) HIF-1α-2723 Target:5′-GGAATGGAGCAAAAGACAATTATTTTA-3′ (SEQ ID NO: 3381)5′-AUGGAGCAAAAGACAAUUAUUUUaa-3′ (SEQ ID NO: 2858)3′-CUUACCUCGUUUUCUGUUAAUAAAAUU-5′ (SEQ ID NO: 2334) HIF-1α-2724 Target:5′-GAATGGAGCAAAAGACAATTATTTTAA-3′ (SEQ ID NO: 3382)5′-UGGAGCAAAAGACAAUUAUUUUAat-3′ (SEQ ID NO: 2859)3′-UUACCUCGUUUUCUGUUAAUAAAAUUA-5′ (SEQ ID NO: 2335) HIF-1α-2725 Target:5′-AATGGAGCAAAAGACAATTATTTTAAT-3′ (SEQ ID NO: 3383)5′-GGAGCAAAAGACAAUUAUUUUAAta-3′ (SEQ ID NO: 2860)3′-UACCUCGUUUUCUGUUAAUAAAAUUAU-5′ (SEQ ID NO: 2336) HIF-1α-2726 Target:5′-ATGGAGCAAAAGACAATTATTTTAATA-3′ (SEQ ID NO: 3384)5′-AAUUAUUUUAAUACCCUCUGAUUta-3′ (SEQ ID NO: 2861)3′-UGUUAAUAAAAUUAUGGGAGACUAAAU-5′ (SEQ ID NO: 2337) HIF-1α-2738 Target:5′-ACAATTATTTTAATACCCTCTGATTTA-3′ (SEQ ID NO: 3385)5′-AUUAUUUUAAUACCCUCUGAUUUag-3′ (SEQ ID NO: 2862)3′-GUUAAUAAAAUUAUGGGAGACUAAAUC-5′ (SEQ ID NO: 2338) HIF-1α-2739 Target:5′-CAATTATTTTAATACCCTCTGATTTAG-3′ (SEQ ID NO: 3386)5′-UUAUUUUAAUACCCUCUGAUUUAgc-3′ (SEQ ID NO: 2863)3′-UUAAUAAAAUUAUGGGAGACUAAAUCG-5′ (SEQ ID NO: 2339) HIF-1α-2740 Target:5′-AATTATTTTAATACCCTCTGATTTAGC-3′ (SEQ ID NO: 3387)5′-AUUUUAAUACCCUCUGAUUUAGCat-3′ (SEQ ID NO: 2864)3′-AAUAAAAUUAUGGGAGACUAAAUCGUA-5′ (SEQ ID NO: 2340) HIF-1α-2742 Target:5′-TTATTTTAATACCCTCTGATTTAGCAT-3′ (SEQ ID NO: 3388)5′-UUUUAAUACCCUCUGAUUUAGCAtg-3′ (SEQ ID NO: 2865)3′-AUAAAAUUAUGGGAGACUAAAUCGUAC-5′ (SEQ ID NO: 2341) HIF-1α-2743 Target:5′-TATTTTAATACCCTCTGATTTAGCATG-3′ (SEQ ID NO: 3389)5′-UGGGGCAAUCAAUGGAUGAAAGUgg-3′ (SEQ ID NO: 2866)3′-CGACCCCGUUAGUUACCUACUUUCACC-5′ (SEQ ID NO: 2342) HIF-1α-2776 Target:5′-GCTGGGGCAATCAATGGATGAAAGTGG-3′ (SEQ ID NO: 3390)5′-CAAUCAAUGGAUGAAAGUGGAUUac-3′ (SEQ ID NO: 2867)3′-CCGUUAGUUACCUACUUUCACCUAAUG-5′ (SEQ ID NO: 2343) HIF-1α-2781 Target:5′-GGCAATCAATGGATGAAAGTGGATTAC-3′ (SEQ ID NO: 3391)5′-AGUUAUGAUUGUGAAGUUAAUGCtc-3′ (SEQ ID NO: 2868)3′-GGUCAAUACUAACACUUCAAUUACGAG-5′ (SEQ ID NO: 2344) HIF-1α-2817 Target:5′-CCAGTTATGATTGTGAAGTTAATGCTC-3′ (SEQ ID NO: 3392)5′-GUUAUGAUUGUGAAGUUAAUGCUcc-3′ (SEQ ID NO: 2869)3′-GUCAAUACUAACACUUCAAUUACGAGG-5′ (SEQ ID NO: 2345) HIF-1α-2818 Target:5′-CAGTTATGATTGTGAAGTTAATGCTCC-3′ (SEQ ID NO: 3393)5′-UGUGAAGUUAAUGCUCCUAUACAag-3′ (SEQ ID NO: 2870)3′-UAACACUUCAAUUACGAGGAUAUGUUC-5′ (SEQ ID NO: 2346) HIF-1α-2826 Target:5′-ATTGTGAAGTTAATGCTCCTATACAAG-3′ (SEQ ID NO: 3394)5′-AAGUUAAUGCUCCUAUACAAGGCag-3′ (SEQ ID NO: 2871)3′-ACUUCAAUUACGAGGAUAUGUUCCGUC-5′ (SEQ ID NO: 2347) HIF-1α-2830 Target:5′-TGAAGTTAATGCTCCTATACAAGGCAG-3′ (SEQ ID NO: 3395)5′-AGGGUGAAGAAUUACUCAGAGCUtt-3′ (SEQ ID NO: 2872)3′-CGUCCCACUUCUUAAUGAGUCUCGAAA-5′ (SEQ ID NO: 2348) HIF-1α-2869 Target:5′-GCAGGGTGAAGAATTACTCAGAGCTTT-3′ (SEQ ID NO: 3396)5′-AAGAAUUACUCAGAGCUUUGGAUca-3′ (SEQ ID NO: 2873)3′-ACUUCUUAAUGAGUCUCGAAACCUAGU-5′ (SEQ ID NO: 2349) HIF-1α-2875 Target:5′-TGAAGAATTACTCAGAGCTTTGGATCA-3′ (SEQ ID NO: 3397)5′-GAAUUACUCAGAGCUUUGGAUCAag-3′ (SEQ ID NO: 2874)3′-UUCUUAAUGAGUCUCGAAACCUAGUUC-5′ (SEQ ID NO: 2350) HIF-1α-2877 Target:5′-AAGAATTACTCAGAGCTTTGGATCAAG-3′ (SEQ ID NO: 3398)5′-CAGAGCUUUGGAUCAAGUUAACUga-3′ (SEQ ID NO: 2875)3′-GAGUCUCGAAACCUAGUUCAAUUGACU-5′ (SEQ ID NO: 2351) HIF-1α-2885 Target:5′-CTCAGAGCTTTGGATCAAGTTAACTGA-3′ (SEQ ID NO: 3399)5′-AGUUAACUGAGCUUUUUCUUAAUtt-3′ (SEQ ID NO: 2876)3′-GUUCAAUUGACUCGAAAAAGAAUUAAA-5′ (SEQ ID NO: 2352) HIF-1α-2900 Target:5′-CAAGTTAACTGAGCTTTTTCTTAATTT-3′ (SEQ ID NO: 3400)5′-UUAACUGAGCUUUUUCUUAAUUUca-3′ (SEQ ID NO: 2877)3′-UCAAUUGACUCGAAAAAGAAUUAAAGU-5′ (SEQ ID NO: 2353) HIF-1α-2902 Target:5′-AGTTAACTGAGCTTTTTCTTAATTTCA-3′ (SEQ ID NO: 3401)5′-UUUUCUUAAUUUCAUUCCUUUUUtt-3′ (SEQ ID NO: 2878)3′-GAAAAAGAAUUAAAGUAAGGAAAAAAA-5′ (SEQ ID NO: 2354) HIF-1α-2913 Target:5′-CTTTTTCTTAATTTCATTCCTTTTTTT-3′ (SEQ ID NO: 3402)5′-UUAAUUUCAUUCCUUUUUUUGGAca-3′ (SEQ ID NO: 2879)3′-AGAAUUAAAGUAAGGAAAAAAACCUGU-5′ (SEQ ID NO: 2355) HIF-1α-2918 Target:5′-TCTTAATTTCATTCCTTTTTTTGGACA-3′ (SEQ ID NO: 3403)5′-AAUUUCAUUCCUUUUUUUGGACAct-3′ (SEQ ID NO: 2880)3′-AAUUAAAGUAAGGAAAAAAACCUGUGA-5′ (SEQ ID NO: 2356) HIF-1α-2920 Target:5′-TTAATTTCATTCCTTTTTTTGGACACT-3′ (SEQ ID NO: 3404)5′-CUGGUGGCUCAUUACCUAAAGCAgt-3′ (SEQ ID NO: 2881)3′-GUGACCACCGAGUAAUGGAUUUCGUCA-5′ (SEQ ID NO: 2357) HIF-1α-2943 Target:5′-CACTGGTGGCTCATTACCTAAAGCAGT-3′ (SEQ ID NO: 3405)5′-CAUUACCUAAAGCAGUCUAUUUAta-3′ (SEQ ID NO: 2882)3′-GAGUAAUGGAUUUCGUCAGAUAAAUAU-5′ (SEQ ID NO: 2358) HIF-1α-2952 Target:5′-CTCATTACCTAAAGCAGTCTATTTATA-3′ (SEQ ID NO: 3406)5′-AUUACCUAAAGCAGUCUAUUUAUat-3′ (SEQ ID NO: 2883)3′-AGUAAUGGAUUUCGUCAGAUAAAUAUA-5′ (SEQ ID NO: 2359) HIF-1α-2953 Target:5′-TCATTACCTAAAGCAGTCTATTTATAT-3′ (SEQ ID NO: 3407)5′-CUAAAGCAGUCUAUUUAUAUUUUct-3′ (SEQ ID NO: 2884)3′-UGGAUUUCGUCAGAUAAAUAUAAAAGA-5′ (SEQ ID NO: 2360) HIF-1α-2958 Target:5′-ACCTAAAGCAGTCTATTTATATTTTCT-3′ (SEQ ID NO: 3408)5′-AAAGCAGUCUAUUUAUAUUUUCUac-3′ (SEQ ID NO: 2885)3′-GAUUUCGUCAGAUAAAUAUAAAAGAUG-5′ (SEQ ID NO: 2361) HIF-1α-2960 Target:5′-CTAAAGCAGTCTATTTATATTTTCTAC-3′ (SEQ ID NO: 3409)5′-UUUAUAUUUUCUACAUCUAAUUUta-3′ (SEQ ID NO: 2886)3′-AUAAAUAUAAAAGAUGUAGAUUAAAAU-5′ (SEQ ID NO: 2362) HIF-1α-2971 Target:5′-TATTTATATTTTCTACATCTAATTTTA-3′ (SEQ ID NO: 3410)5′-UUAUAUUUUCUACAUCUAAUUUUag-3′ (SEQ ID NO: 2887)3′-UAAAUAUAAAAGAUGUAGAUUAAAAUC-5′ (SEQ ID NO: 2363) HIF-1α-2972 Target:5′-ATTTATATTTTCTACATCTAATTTTAG-3′ (SEQ ID NO: 3411)5′-UAUAUUUUCUACAUCUAAUUUUAga-3′ (SEQ ID NO: 2888)3′-AAAUAUAAAAGAUGUAGAUUAAAAUCU-5′ (SEQ ID NO: 2364) HIF-1α-2973 Target:5′-TTTATATTTTCTACATCTAATTTTAGA-3′ (SEQ ID NO: 3412)5′-UAUUUUCUACAUCUAAUUUUAGAag-3′ (SEQ ID NO: 2889)3′-AUAUAAAAGAUGUAGAUUAAAAUCUUC-5′ (SEQ ID NO: 2365) HIF-1α-2975 Target:5′-TATATTTTCTACATCTAATTTTAGAAG-3′ (SEQ ID NO: 3413)5′-AUUUUCUACAUCUAAUUUUAGAAgc-3′ (SEQ ID NO: 2890)3′-UAUAAAAGAUGUAGAUUAAAAUCUUCG-5′ (SEQ ID NO: 2366) HIF-1α-2976 Target:5′-ATATTTTCTACATCTAATTTTAGAAGC-3′ (SEQ ID NO: 3414)5′-CUGGCUACAAUACUGCACAAACUtg-3′ (SEQ ID NO: 2891)3′-CGGACCGAUGUUAUGACGUGUUUGAAC-5′ (SEQ ID NO: 2367) HIF-1α-3001 Target:5′-GCCTGGCTACAATACTGCACAAACTTG-3′ (SEQ ID NO: 3415)5′-CUUGGUUAGUUCAAUUUUGAUCCcc-3′ (SEQ ID NO: 2892)3′-UUGAACCAAUCAAGUUAAAACUAGGGG-5′ (SEQ ID NO: 2368) HIF-1α-3022 Target:5′-AACTTGGTTAGTTCAATTTTGATCCCC-3′ (SEQ ID NO: 3416)5′-AGUUCAAUUUUGAUCCCCUUUCUac-3′ (SEQ ID NO: 2893)3′-AAUCAAGUUAAAACUAGGGGAAAGAUG-5′ (SEQ ID NO: 2369) HIF-1α-3029 Target:5′-TTAGTTCAATTTTGATCCCCTTTCTAC-3′ (SEQ ID NO: 3417)5′-UUUGAUCCCCUUUCUACUUAAUUta-3′ (SEQ ID NO: 2894)3′-UAAAACUAGGGGAAAGAUGAAUUAAAU-5′ (SEQ ID NO: 2370) HIF-1α-3037 Target:5′-ATTTTGATCCCCTTTCTACTTAATTTA-3′ (SEQ ID NO: 3418)5′-UUGAUCCCCUUUCUACUUAAUUUac-3′ (SEQ ID NO: 2895)3′-AAAACUAGGGGAAAGAUGAAUUAAAUG-5′ (SEQ ID NO: 2371) HIF-1α-3038 Target:5′-TTTTGATCCCCTTTCTACTTAATTTAC-3′ (SEQ ID NO: 3419)5′-UGAUCCCCUUUCUACUUAAUUUAca-3′ (SEQ ID NO: 2896)3′-AAACUAGGGGAAAGAUGAAUUAAAUGU-5′ (SEQ ID NO: 2372) HIF-1α-3039 Target:5′-TTTGATCCCCTTTCTACTTAATTTACA-3′ (SEQ ID NO: 3420)5′-CUUUCUACUUAAUUUACAUUAAUgc-3′ (SEQ ID NO: 2897)3′-GGGAAAGAUGAAUUAAAUGUAAUUACG-5′ (SEQ ID NO: 2373) HIF-1α-3046 Target:5′-CCCTTTCTACTTAATTTACATTAATGC-3′ (SEQ ID NO: 3421)5′-AAUUUACAUUAAUGCUCUUUUUUag-3′ (SEQ ID NO: 2898)3′-AAUUAAAUGUAAUUACGAGAAAAAAUC-5′ (SEQ ID NO: 2374) HIF-1α-3056 Target:5′-TTAATTTACATTAATGCTCTTTTTTAG-3′ (SEQ ID NO: 3422)5′-AUUUACAUUAAUGCUCUUUUUUAgt-3′ (SEQ ID NO: 2899)3′-AUUAAAUGUAAUUACGAGAAAAAAUCA-5′ (SEQ ID NO: 2375) HIF-1α-3057 Target:5′-TAATTTACATTAATGCTCTTTTTTAGT-3′ (SEQ ID NO: 3423)5′-AUUAAUGCUCUUUUUUAGUAUGUtc-3′ (SEQ ID NO: 2900)3′-UGUAAUUACGAGAAAAAAUCAUACAAG-5′ (SEQ ID NO: 2376) HIF-1α-3063 Target:5′-ACATTAATGCTCTTTTTTAGTATGTTC-3′ (SEQ ID NO: 3424)5′-UUAAUGCUCUUUUUUAGUAUGUUct-3′ (SEQ ID NO: 2901)3′-GUAAUUACGAGAAAAAAUCAUACAAGA-5′ (SEQ ID NO: 2377) HIF-1α-3064 Target:5′-CATTAATGCTCTTTTTTAGTATGTTCT-3′ (SEQ ID NO: 3425)5′-AAUGCUCUUUUUUAGUAUGUUCUtt-3′ (SEQ ID NO: 2902)3′-AAUUACGAGAAAAAAUCAUACAAGAAA-5′ (SEQ ID NO: 2378) HIF-1α-3066 Target:5′-TTAATGCTCTTTTTTAGTATGTTCTTT-3′ (SEQ ID NO: 3426)5′-UUUUUAGUAUGUUCUUUAAUGCUgg-3′ (SEQ ID NO: 2903)3′-GAAAAAAUCAUACAAGAAAUUACGACC-5′ (SEQ ID NO: 2379) HIF-1α-3074 Target:5′-CTTTTTTAGTATGTTCTTTAATGCTGG-3′ (SEQ ID NO: 3427)5′-UAGUAUGUUCUUUAAUGCUGGAUca-3′ (SEQ ID NO: 2904)3′-AAAUCAUACAAGAAAUUACGACCUAGU-5′ (SEQ ID NO: 2380) HIF-1α-3078 Target:5′-TTTAGTATGTTCTTTAATGCTGGATCA-3′ (SEQ ID NO: 3428)5′-AGUAUGUUCUUUAAUGCUGGAUCac-3′ (SEQ ID NO: 2905)3′-AAUCAUACAAGAAAUUACGACCUAGUG-5′ (SEQ ID NO: 2381) HIF-1α-3079 Target:5′-TTAGTATGTTCTTTAATGCTGGATCAC-3′ (SEQ ID NO: 3429)5′-GUAUGUUCUUUAAUGCUGGAUCAca-3′ (SEQ ID NO: 2906)3′-AUCAUACAAGAAAUUACGACCUAGUGU-5′ (SEQ ID NO: 2382) HIF-1α-3080 Target:5′-TAGTATGTTCTTTAATGCTGGATCACA-3′ (SEQ ID NO: 3430)5′-CAGACAGCUCAUUUUCUCAGUUUtt-3′ (SEQ ID NO: 2907)3′-GUGUCUGUCGAGUAAAAGAGUCAAAAA-5′ (SEQ ID NO: 2383) HIF-1α-3103 Target:5′-CACAGACAGCTCATTTTCTCAGTTTTT-3′ (SEQ ID NO: 3431)5′-CAUUUUCUCAGUUUUUUGGUAUUta-3′ (SEQ ID NO: 2908)3′-GAGUAAAAGAGUCAAAAAACCAUAAAU-5′ (SEQ ID NO: 2384) HIF-1α-3112 Target:5′-CTCATTTTCTCAGTTTTTTGGTATTTA-3′ (SEQ ID NO: 3432)5′-AUUUUCUCAGUUUUUUGGUAUUUaa-3′ (SEQ ID NO: 2909)3′-AGUAAAAGAGUCAAAAAACCAUAAAUU-5′ (SEQ ID NO: 2385) HIF-1α-3113 Target:5′-TCATTTTCTCAGTTTTTTGGTATTTAA-3′ (SEQ ID NO: 3433)5′-UUUUCUCAGUUUUUUGGUAUUUAaa-3′ (SEQ ID NO: 2910)3′-GUAAAAGAGUCAAAAAACCAUAAAUUU-5′ (SEQ ID NO: 2386) HIF-1α-3114 Target:5′-CATTTTCTCAGTTTTTTGGTATTTAAA-3′ (SEQ ID NO: 3434)5′-UUUUUGGUAUUUAAACCAUUGCAtt-3′ (SEQ ID NO: 2911)3′-CAAAAAACCAUAAAUUUGGUAACGUAA-5′ (SEQ ID NO: 2387) HIF-1α-3124 Target:5′-GTTTTTTGGTATTTAAACCATTGCATT-3′ (SEQ ID NO: 3435)5′-UGGUAUUUAAACCAUUGCAUUGCag-3′ (SEQ ID NO: 2912)3′-AAACCAUAAAUUUGGUAACGUAACGUC-5′ (SEQ ID NO: 2388) HIF-1α-3128 Target:5′-TTTGGTATTTAAACCATTGCATTGCAG-3′ (SEQ ID NO: 3436)5′-GGUAUUUAAACCAUUGCAUUGCAgt-3′ (SEQ ID NO: 2913)3′-AACCAUAAAUUUGGUAACGUAACGUCA-5′ (SEQ ID NO: 2389) HIF-1α-3129 Target:5′-TTGGTATTTAAACCATTGCATTGCAGT-3′ (SEQ ID NO: 3437)5′-UUAAACCAUUGCAUUGCAGUAGCat-3′ (SEQ ID NO: 2914)3′-UAAAUUUGGUAACGUAACGUCAUCGUA-5′ (SEQ ID NO: 2390) HIF-1α-3134 Target:5′-ATTTAAACCATTGCATTGCAGTAGCAT-3′ (SEQ ID NO: 3438)5′-AUUGCAGUAGCAUCAUUUUAAAAaa-3′ (SEQ ID NO: 2915)3′-CGUAACGUCAUCGUAGUAAAAUUUUUU-5′ (SEQ ID NO: 2391) HIF-1α-3146 Target:5′-GCATTGCAGTAGCATCATTTTAAAAAA-3′ (SEQ ID NO: 3439)5′-AGUAGCAUCAUUUUAAAAAAUGCac-3′ (SEQ ID NO: 2916)3′-CGUCAUCGUAGUAAAAUUUUUUACGUG-5′ (SEQ ID NO: 2392) HIF-1α-3151 Target:5′-GCAGTAGCATCATTTTAAAAAATGCAC-3′ (SEQ ID NO: 3440)5′-GUAGCAUCAUUUUAAAAAAUGCAcc-3′ (SEQ ID NO: 2917)3′-GUCAUCGUAGUAAAAUUUUUUACGUGG-5′ (SEQ ID NO: 2393) HIF-1α-3152 Target:5′-CAGTAGCATCATTTTAAAAAATGCACC-3′ (SEQ ID NO: 3441)5′-CAUUUUAAAAAAUGCACCUUUUUat-3′ (SEQ ID NO: 2918)3′-UAGUAAAAUUUUUUACGUGGAAAAAUA-5′ (SEQ ID NO: 2394) HIF-1α-3159 Target:5′-ATCATTTTAAAAAATGCACCTTTTTAT-3′ (SEQ ID NO: 3442)5′-AUUUUAAAAAAUGCACCUUUUUAtt-3′ (SEQ ID NO: 2919)3′-AGUAAAAUUUUUUACGUGGAAAAAUAA-5′ (SEQ ID NO: 2395) HIF-1α-3160 Target:5′-TCATTTTAAAAAATGCACCTTTTTATT-3′ (SEQ ID NO: 3443)5′-UUUUAAAAAAUGCACCUUUUUAUtt-3′ (SEQ ID NO: 2920)3′-GUAAAAUUUUUUACGUGGAAAAAUAAA-5′ (SEQ ID NO: 2396) HIF-1α-3161 Target:5′-CATTTTAAAAAATGCACCTTTTTATTT-3′ (SEQ ID NO: 3444)5′-UUUAAAAAAUGCACCUUUUUAUUta-3′ (SEQ ID NO: 2921)3′-UAAAAUUUUUUACGUGGAAAAAUAAAU-5′ (SEQ ID NO: 2397) HIF-1α-3162 Target:5′-ATTTTAAAAAATGCACCTTTTTATTTA-3′ (SEQ ID NO: 3445)5′-UUAAAAAAUGCACCUUUUUAUUUat-3′ (SEQ ID NO: 2922)3′-AAAAUUUUUUACGUGGAAAAAUAAAUA-5′ (SEQ ID NO: 2398) HIF-1α-3163 Target:5′-TTTTAAAAAATGCACCTTTTTATTTAT-3′ (SEQ ID NO: 3446)5′-UAAAAAAUGCACCUUUUUAUUUAtt-3′ (SEQ ID NO: 2923)3′-AAAUUUUUUACGUGGAAAAAUAAAUAA-5′ (SEQ ID NO: 2399) HIF-1α-3164 Target:5′-TTTAAAAAATGCACCTTTTTATTTATT-3′ (SEQ ID NO: 3447)5′-AAAAAUGCACCUUUUUAUUUAUUta-3′ (SEQ ID NO: 2924)3′-AUUUUUUACGUGGAAAAAUAAAUAAAU-5′ (SEQ ID NO: 2400) HIF-1α-3166 Target:5′-TAAAAAATGCACCTTTTTATTTATTTA-3′ (SEQ ID NO: 3448)5′-AAAUGCACCUUUUUAUUUAUUUAtt-3′ (SEQ ID NO: 2925)3′-UUUUUACGUGGAAAAAUAAAUAAAUAA-5′ (SEQ ID NO: 2401) HIF-1α-3168 Target:5′-AAAAATGCACCTTTTTATTTATTTATT-3′ (SEQ ID NO: 3449)5′-CUUUUUAUUUAUUUAUUUUUGGCta-3′ (SEQ ID NO: 2926)3′-UGGAAAAAUAAAUAAAUAAAAACCGAU-5′ (SEQ ID NO: 2402) HIF-1α-3176 Target:5′-ACCTTTTTATTTATTTATTTTTGGCTA-3′ (SEQ ID NO: 3450)5′-AUUUAUUUAUUUUUGGCUAGGGAgt-3′ (SEQ ID NO: 2927)3′-AAUAAAUAAAUAAAAACCGAUCCCUCA-5′ (SEQ ID NO: 2403) HIF-1α-3182 Target:5′-TTATTTATTTATTTTTGGCTAGGGAGT-3′ (SEQ ID NO: 3451)5′-UUAUUUAUUUUUGGCUAGGGAGUtt-3′ (SEQ ID NO: 2928)3′-UAAAUAAAUAAAAACCGAUCCCUCAAA-5′ (SEQ ID NO: 2404) HIF-1α-3184 Target:5′-ATTTATTTATTTTTGGCTAGGGAGTTT-3′ (SEQ ID NO: 3452)5′-UAUUUAUUUUUGGCUAGGGAGUUta-3′ (SEQ ID NO: 2929)3′-AAAUAAAUAAAAACCGAUCCCUCAAAU-5′ (SEQ ID NO: 2405) HIF-1α-3185 Target:5′-TTTATTTATTTTTGGCTAGGGAGTTTA-3′ (SEQ ID NO: 3453)5′-AUUUAUUUUUGGCUAGGGAGUUUat-3′ (SEQ ID NO: 2930)3′-AAUAAAUAAAAACCGAUCCCUCAAAUA-5′ (SEQ ID NO: 2406) HIF-1α-3186 Target:5′-TTATTTATTTTTGGCTAGGGAGTTTAT-3′ (SEQ ID NO: 3454)5′-UUUAUUUUUGGCUAGGGAGUUUAtc-3′ (SEQ ID NO: 2931)3′-AUAAAUAAAAACCGAUCCCUCAAAUAG-5′ (SEQ ID NO: 2407) HIF-1α-3187 Target:5′-TATTTATTTTTGGCTAGGGAGTTTATC-3′ (SEQ ID NO: 3455)5′-GGAGUUUAUCCCUUUUUCGAAUUat-3′ (SEQ ID NO: 2932)3′-UCCCUCAAAUAGGGAAAAAGCUUAAUA-5′ (SEQ ID NO: 2408) HIF-1α-3202 Target:5′-AGGGAGTTTATCCCTTTTTCGAATTAT-3′ (SEQ ID NO: 3456)5′-GAGUUUAUCCCUUUUUCGAAUUAtt-3′ (SEQ ID NO: 2933)3′-CCCUCAAAUAGGGAAAAAGCUUAAUAA-5′ (SEQ ID NO: 2409) HIF-1α-3203 Target:5′-GGGAGTTTATCCCTTTTTCGAATTATT-3′ (SEQ ID NO: 3457)5′-AGUUUAUCCCUUUUUCGAAUUAUtt-3′ (SEQ ID NO: 2934)3′-CCUCAAAUAGGGAAAAAGCUUAAUAAA-5′ (SEQ ID NO: 2410) HIF-1α-3204 Target:5′-GGAGTTTATCCCTTTTTCGAATTATTT-3′ (SEQ ID NO: 3458)5′-GUUUAUCCCUUUUUCGAAUUAUUtt-3′ (SEQ ID NO: 2935)3′-CUCAAAUAGGGAAAAAGCUUAAUAAAA-5′ (SEQ ID NO: 2411) HIF-1α-3205 Target:5′-GAGTTTATCCCTTTTTCGAATTATTTT-3′ (SEQ ID NO: 3459)5′-UUUAUCCCUUUUUCGAAUUAUUUtt-3′ (SEQ ID NO: 2936)3′-UCAAAUAGGGAAAAAGCUUAAUAAAAA-5′ (SEQ ID NO: 2412) HIF-1α-3206 Target:5′-AGTTTATCCCTTTTTCGAATTATTTTT-3′ (SEQ ID NO: 3460)5′-UUAUCCCUUUUUCGAAUUAUUUUta-3′ (SEQ ID NO: 2937)3′-CAAAUAGGGAAAAAGCUUAAUAAAAAU-5′ (SEQ ID NO: 2413) HIF-1α-3207 Target:5′-GTTTATCCCTTTTTCGAATTATTTTTA-3′ (SEQ ID NO: 3461)5′-CGAAUUAUUUUUAAGAAGAUGCCaa-3′ (SEQ ID NO: 2938)3′-AAGCUUAAUAAAAAUUCUUCUACGGUU-5′ (SEQ ID NO: 2414) HIF-1α-3219 Target:5′-TTCGAATTATTTTTAAGAAGATGCCAA-3′ (SEQ ID NO: 3462)5′-UAUUUUUAAGAAGAUGCCAAUAUaa-3′ (SEQ ID NO: 2939)3′-UAAUAAAAAUUCUUCUACGGUUAUAUU-5′ (SEQ ID NO: 2415) HIF-1α-3224 Target:5′-ATTATTTTTAAGAAGATGCCAATATAA-3′ (SEQ ID NO: 3463)5′-AUUUUUAAGAAGAUGCCAAUAUAat-3′ (SEQ ID NO: 2940)3′-AAUAAAAAUUCUUCUACGGUUAUAUUA-5′ (SEQ ID NO: 2416) HIF-1α-3225 Target:5′-TTATTTTTAAGAAGATGCCAATATAAT-3′ (SEQ ID NO: 3464)5′-UUUUAAGAAGAUGCCAAUAUAAUtt-3′ (SEQ ID NO: 2941)3′-UAAAAAUUCUUCUACGGUUAUAUUAAA-5′ (SEQ ID NO: 2417) HIF-1α-3227 Target:5′-ATTTTTAAGAAGATGCCAATATAATTT-3′ (SEQ ID NO: 3465)5′-UUUAAGAAGAUGCCAAUAUAAUUtt-3′ (SEQ ID NO: 2942)3′-AAAAAUUCUUCUACGGUUAUAUUAAAA-5′ (SEQ ID NO: 2418) HIF-1α-3228 Target:5′-TTTTTAAGAAGATGCCAATATAATTTT-3′ (SEQ ID NO: 3466)5′-UAAGAAGAUGCCAAUAUAAUUUUtg-3′ (SEQ ID NO: 2943)3′-AAAUUCUUCUACGGUUAUAUUAAAAAC-5′ (SEQ ID NO: 2419) HIF-1α-3230 Target:5′-TTTAAGAAGATGCCAATATAATTTTTG-3′ (SEQ ID NO: 3467)5′-AAGAAGAUGCCAAUAUAAUUUUUgt-3′ (SEQ ID NO: 2944)3′-AAUUCUUCUACGGUUAUAUUAAAAACA-5′ (SEQ ID NO: 2420) HIF-1α-3231 Target:5′-TTAAGAAGATGCCAATATAATTTTTGT-3′ (SEQ ID NO: 3468)5′-GAAGAUGCCAAUAUAAUUUUUGUaa-3′ (SEQ ID NO: 2945)3′-UUCUUCUACGGUUAUAUUAAAAACAUU-5′ (SEQ ID NO: 2421) HIF-1α-3233 Target:5′-AAGAAGATGCCAATATAATTTTTGTAA-3′ (SEQ ID NO: 3469)5′-AAGAUGCCAAUAUAAUUUUUGUAag-3′ (SEQ ID NO: 2946)3′-UCUUCUACGGUUAUAUUAAAAACAUUC-5′ (SEQ ID NO: 2422) HIF-1α-3234 Target:5′-AGAAGATGCCAATATAATTTTTGTAAG-3′ (SEQ ID NO: 3470)5′-AGAUGCCAAUAUAAUUUUUGUAAga-3′ (SEQ ID NO: 2947)3′-CUUCUACGGUUAUAUUAAAAACAUUCU-5′ (SEQ ID NO: 2423) HIF-1α-3235 Target:5′-GAAGATGCCAATATAATTTTTGTAAGA-3′ (SEQ ID NO: 3471)5′-AAUAUAAUUUUUGUAAGAAGGCAgt-3′ (SEQ ID NO: 2948)3′-GGUUAUAUUAAAAACAUUCUUCCGUCA-5′ (SEQ ID NO: 2424) HIF-1α-3242 Target:5′-CCAATATAATTTTTGTAAGAAGGCAGT-3′ (SEQ ID NO: 3472)5′-UAAUUUUUGUAAGAAGGCAGUAAcc-3′ (SEQ ID NO: 2949)3′-AUAUUAAAAACAUUCUUCCGUCAUUGG-5′ (SEQ ID NO: 2425) HIF-1α-3246 Target:5′-TATAATTTTTGTAAGAAGGCAGTAACC-3′ (SEQ ID NO: 3473)5′-AUUUUUGUAAGAAGGCAGUAACCtt-3′ (SEQ ID NO: 2950)3′-AUUAAAAACAUUCUUCCGUCAUUGGAA-5′ (SEQ ID NO: 2426) HIF-1α-3248 Target:5′-TAATTTTTGTAAGAAGGCAGTAACCTT-3′ (SEQ ID NO: 3474)5′-CAUGAUCAUAGGCAGUUGAAAAAtt-3′ (SEQ ID NO: 2951)3′-UAGUACUAGUAUCCGUCAACUUUUUAA-5′ (SEQ ID NO: 2427) HIF-1α-3277 Target:5′-ATCATGATCATAGGCAGTTGAAAAATT-3′ (SEQ ID NO: 3475)5′-UGAUCAUAGGCAGUUGAAAAAUUtt-3′ (SEQ ID NO: 2952)3′-GUACUAGUAUCCGUCAACUUUUUAAAA-5′ (SEQ ID NO: 2428) HIF-1α-3279 Target:5′-CATGATCATAGGCAGTTGAAAAATTTT-3′ (SEQ ID NO: 3476)5′-CAUAGGCAGUUGAAAAAUUUUUAca-3′ (SEQ ID NO: 2953)3′-UAGUAUCCGUCAACUUUUUAAAAAUGU-5′ (SEQ ID NO: 2429) HIF-1α-3283 Target:5′-ATCATAGGCAGTTGAAAAATTTTTACA-3′ (SEQ ID NO: 3477)5′-UAGGCAGUUGAAAAAUUUUUACAcc-3′ (SEQ ID NO: 2954)3′-GUAUCCGUCAACUUUUUAAAAAUGUGG-5′ (SEQ ID NO: 2430) HIF-1α-3285 Target:5′-CATAGGCAGTTGAAAAATTTTTACACC-3′ (SEQ ID NO: 3478)5′-UGAAAAAUUUUUACACCUUUUUUtt-3′ (SEQ ID NO: 2955)3′-CAACUUUUUAAAAAUGUGGAAAAAAAA-5′ (SEQ ID NO: 2431) HIF-1α-3293 Target:5′-GTTGAAAAATTTTTACACCTTTTTTTT-3′ (SEQ ID NO: 3479)5′-GAAAAAUUUUUACACCUUUUUUUtc-3′ (SEQ ID NO: 2956)3′-AACUUUUUAAAAAUGUGGAAAAAAAAG-5′ (SEQ ID NO: 2432) HIF-1α-3294 Target:5′-TTGAAAAATTTTTACACCTTTTTTTTC-3′ (SEQ ID NO: 3480)5′-AAAAAUUUUUACACCUUUUUUUUca-3′ (SEQ ID NO: 2957)3′-ACUUUUUAAAAAUGUGGAAAAAAAAGU-5′ (SEQ ID NO: 2433) HIF-1α-3295 Target:5′-TGAAAAATTTTTACACCTTTTTTTTCA-3′ (SEQ ID NO: 3481)5′-AAAAUUUUUACACCUUUUUUUUCac-3′ (SEQ ID NO: 2958)3′-CUUUUUAAAAAUGUGGAAAAAAAAGUG-5′ (SEQ ID NO: 2434) HIF-1α-3296 Target:5′-GAAAAATTTTTACACCTTTTTTTTCAC-3′ (SEQ ID NO: 3482)5′-AAAUUUUUACACCUUUUUUUUCAca-3′ (SEQ ID NO: 2959)3′-UUUUUAAAAAUGUGGAAAAAAAAGUGU-5′ (SEQ ID NO: 2435) HIF-1α-3297 Target:5′-AAAAATTTTTACACCTTTTTTTTCACA-3′ (SEQ ID NO: 3483)5′-UUUUUUUCACAUUUUACAUAAAUaa-3′ (SEQ ID NO: 2960)3′-GAAAAAAAAGUGUAAAAUGUAUUUAUU-5′ (SEQ ID NO: 2436) HIF-1α-3311 Target:5′-CTTTTTTTTCACATTTTACATAAATAA-3′ (SEQ ID NO: 3484)5′-UUUUUUCACAUUUUACAUAAAUAat-3′ (SEQ ID NO: 2961)3′-AAAAAAAAGUGUAAAAUGUAUUUAUUA-5′ (SEQ ID NO: 2437) HIF-1α-3312 Target:5′-TTTTTTTTCACATTTTACATAAATAAT-3′ (SEQ ID NO: 3485)5′-UUUUUCACAUUUUACAUAAAUAAta-3′ (SEQ ID NO: 2962)3′-AAAAAAAGUGUAAAAUGUAUUUAUUAU-5′ (SEQ ID NO: 2438) HIF-1α-3313 Target:5′-TTTTTTTCACATTTTACATAAATAATA-3′ (SEQ ID NO: 3486)5′-UUUUCACAUUUUACAUAAAUAAUaa-3′ (SEQ ID NO: 2963)3′-AAAAAAGUGUAAAAUGUAUUUAUUAUU-5′ (SEQ ID NO: 2439) HIF-1α-3314 Target:5′-TTTTTTCACATTTTACATAAATAATAA-3′ (SEQ ID NO: 3487)5′-CAUUUUACAUAAAUAAUAAUGCUtt-3′ (SEQ ID NO: 2964)3′-GUGUAAAAUGUAUUUAUUAUUACGAAA-5′ (SEQ ID NO: 2440) HIF-1α-3320 Target:5′-CACATTTTACATAAATAATAATGCTTT-3′ (SEQ ID NO: 3488)5′-GUAGCCACAAUUGCACAAUAUAUtt-3′ (SEQ ID NO: 2965)3′-ACCAUCGGUGUUAACGUGUUAUAUAAA-5′ (SEQ ID NO: 2441) HIF-1α-3359 Target:5′-TGGTAGCCACAATTGCACAATATATTT-3′ (SEQ ID NO: 3489)5′-AAUAUAUUUUCUUAAAAAAUACCag-3′ (SEQ ID NO: 2966)3′-UGUUAUAUAAAAGAAUUUUUUAUGGUC-5′ (SEQ ID NO: 2442) HIF-1α-3375 Target:5′-ACAATATATTTTCTTAAAAAATACCAG-3′ (SEQ ID NO: 3490)5′-CUUAAAAAAUACCAGCAGUUACUca-3′ (SEQ ID NO: 2967)3′-AAGAAUUUUUUAUGGUCGUCAAUGAGU-5′ (SEQ ID NO: 2443) HIF-1α-3385 Target:5′-TTCTTAAAAAATACCAGCAGTTACTCA-3′ (SEQ ID NO: 3491)5′-CAGUUACUCAUGGAAUAUAUUCUgc-3′ (SEQ ID NO: 2968)3′-UCGUCAAUGAGUACCUUAUAUAAGACG-5′ (SEQ ID NO: 2444) HIF-1α-3400 Target:5′-AGCAGTTACTCATGGAATATATTCTGC-3′ (SEQ ID NO: 3492)5′-CAUGGAAUAUAUUCUGCGUUUAUaa-3′ (SEQ ID NO: 2969)3′-GAGUACCUUAUAUAAGACGCAAAUAUU-5′ (SEQ ID NO: 2445) HIF-1α-3408 Target:5′-CTCATGGAATATATTCTGCGTTTATAA-3′ (SEQ ID NO: 3493)5′-AUGGAAUAUAUUCUGCGUUUAUAaa-3′ (SEQ ID NO: 2970)3′-AGUACCUUAUAUAAGACGCAAAUAUUU-5′ (SEQ ID NO: 2446) HIF-1α-3409 Target:5′-TCATGGAATATATTCTGCGTTTATAAA-3′ (SEQ ID NO: 3494)5′-UGGAAUAUAUUCUGCGUUUAUAAaa-3′ (SEQ ID NO: 2971)3′-GUACCUUAUAUAAGACGCAAAUAUUUU-5′ (SEQ ID NO: 2447) HIF-1α-3410 Target:5′-CATGGAATATATTCTGCGTTTATAAAA-3′ (SEQ ID NO: 3495)5′-GGAAUAUAUUCUGCGUUUAUAAAac-3′ (SEQ ID NO: 2972)3′-UACCUUAUAUAAGACGCAAAUAUUUUG-5′ (SEQ ID NO: 2448) HIF-1α-3411 Target:5′-ATGGAATATATTCTGCGTTTATAAAAC-3′ (SEQ ID NO: 3496)5′-GAAUAUAUUCUGCGUUUAUAAAAct-3′ (SEQ ID NO: 2973)3′-ACCUUAUAUAAGACGCAAAUAUUUUGA-5′ (SEQ ID NO: 2449) HIF-1α-3412 Target:5′-TGGAATATATTCTGCGTTTATAAAACT-3′ (SEQ ID NO: 3497)5′-AAUAUAUUCUGCGUUUAUAAAACta-3′ (SEQ ID NO: 2974)3′-CCUUAUAUAAGACGCAAAUAUUUUGAU-5′ (SEQ ID NO: 2450) HIF-1α-3413 Target:5′-GGAATATATTCTGCGTTTATAAAACTA-3′ (SEQ ID NO: 3498)5′-AUAUAUUCUGCGUUUAUAAAACUag-3′ (SEQ ID NO: 2975)3′-CUUAUAUAAGACGCAAAUAUUUUGAUC-5′ (SEQ ID NO: 2451) HIF-1α-3414 Target:5′-GAATATATTCTGCGTTTATAAAACTAG-3′ (SEQ ID NO: 3499)5′-AUAAAACUAGUUUUUAAGAAGAAat-3′ (SEQ ID NO: 2976)3′-AAUAUUUUGAUCAAAAAUUCUUCUUUA-5′ (SEQ ID NO: 2452) HIF-1α-3429 Target:5′-TTATAAAACTAGTTTTTAAGAAGAAAT-3′ (SEQ ID NO: 3500)5′-CUAGUUUUUAAGAAGAAAUUUUUtt-3′ (SEQ ID NO: 2977)3′-UUGAUCAAAAAUUCUUCUUUAAAAAAA-5′ (SEQ ID NO: 2453) HIF-1α-3435 Target:5′-AACTAGTTTTTAAGAAGAAATTTTTTT-3′ (SEQ ID NO: 3501)5′-UAGUUUUUAAGAAGAAAUUUUUUtt-3′ (SEQ ID NO: 2978)3′-UGAUCAAAAAUUCUUCUUUAAAAAAAA-5′ (SEQ ID NO: 2454) HIF-1α-3436 Target:5′-ACTAGTTTTTAAGAAGAAATTTTTTTT-3′ (SEQ ID NO: 3502)5′-AGUUUUUAAGAAGAAAUUUUUUUtg-3′ (SEQ ID NO: 2979)3′-GAUCAAAAAUUCUUCUUUAAAAAAAAC-5′ (SEQ ID NO: 2455) HIF-1α-3437 Target:5′-CTAGTTTTTAAGAAGAAATTTTTTTTG-3′ (SEQ ID NO: 3503)5′-GUUUUUAAGAAGAAAUUUUUUUUgg-3′ (SEQ ID NO: 2980)3′-AUCAAAAAUUCUUCUUUAAAAAAAACC-5′ (SEQ ID NO: 2456) HIF-1α-3438 Target:5′-TAGTTTTTAAGAAGAAATTTTTTTTGG-3′ (SEQ ID NO: 3504)5′-UUUAAGAAGAAAUUUUUUUUGGCct-3′ (SEQ ID NO: 2981)3′-AAAAAUUCUUCUUUAAAAAAAACCGGA-5′ (SEQ ID NO: 2457) HIF-1α-3441 Target:5′-TTTTTAAGAAGAAATTTTTTTTGGCCT-3′ (SEQ ID NO: 3505)5′-AAGAAAUUUUUUUUGGCCUAUGAaa-3′ (SEQ ID NO: 2982)3′-UCUUCUUUAAAAAAAACCGGAUACUUU-5′ (SEQ ID NO: 2458) HIF-1α-3447 Target:5′-AGAAGAAATTTTTTTTGGCCTATGAAA-3′ (SEQ ID NO: 3506)5′-GAAAUUUUUUUUGGCCUAUGAAAtt-3′ (SEQ ID NO: 2983)3′-UUCUUUAAAAAAAACCGGAUACUUUAA-5′ (SEQ ID NO: 2459) HIF-1α-3449 Target:5′-AAGAAATTTTTTTTGGCCTATGAAATT-3′ (SEQ ID NO: 3507)5′-AAUUUUUUUUGGCCUAUGAAAUUgt-3′ (SEQ ID NO: 2984)3′-CUUUAAAAAAAACCGGAUACUUUAACA-5′ (SEQ ID NO: 2460) HIF-1α-3451 Target:5′-GAAATTTTTTTTGGCCTATGAAATTGT-3′ (SEQ ID NO: 3508)5′-UUUUUUUUGGCCUAUGAAAUUGUta-3′ (SEQ ID NO: 2985)3′-UUAAAAAAAACCGGAUACUUUAACAAU-5′ (SEQ ID NO: 2461) HIF-1α-3453 Target:5′-AATTTTTTTTGGCCTATGAAATTGTTA-3′ (SEQ ID NO: 3509)5′-UUUUUGGCCUAUGAAAUUGUUAAac-3′ (SEQ ID NO: 2986)3′-AAAAAAACCGGAUACUUUAACAAUUUG-5′ (SEQ ID NO: 2462) HIF-1α-3456 Target:5′-TTTTTTTGGCCTATGAAATTGTTAAAC-3′ (SEQ ID NO: 3510)5′-UUUUGGCCUAUGAAAUUGUUAAAcc-3′ (SEQ ID NO: 2987)3′-AAAAAACCGGAUACUUUAACAAUUUGG-5′ (SEQ ID NO: 2463) HIF-1α-3457 Target:5′-TTTTTTGGCCTATGAAATTGTTAAACC-3′ (SEQ ID NO: 3511)5′-UUUGGCCUAUGAAAUUGUUAAACct-3′ (SEQ ID NO: 2988)3′-AAAAACCGGAUACUUUAACAAUUUGGA-5′ (SEQ ID NO: 2464) HIF-1α-3458 Target:5′-TTTTTGGCCTATGAAATTGTTAAACCT-3′ (SEQ ID NO: 3512)5′-UUGGCCUAUGAAAUUGUUAAACCtg-3′ (SEQ ID NO: 2989)3′-AAAACCGGAUACUUUAACAAUUUGGAC-5′ (SEQ ID NO: 2465) HIF-1α-3459 Target:5′-TTTTGGCCTATGAAATTGTTAAACCTG-3′ (SEQ ID NO: 3513)5′-CUAUGAAAUUGUUAAACCUGGAAca-3′ (SEQ ID NO: 2990)3′-CGGAUACUUUAACAAUUUGGACCUUGU-5′ (SEQ ID NO: 2466) HIF-1α-3464 Target:5′-GCCTATGAAATTGTTAAACCTGGAACA-3′ (SEQ ID NO: 3514)5′-AUGAAAUUGUUAAACCUGGAACAtg-3′ (SEQ ID NO: 2991)3′-GAUACUUUAACAAUUUGGACCUUGUAC-5′ (SEQ ID NO: 2467) HIF-1α-3466 Target:5′-CTATGAAATTGTTAAACCTGGAACATG-3′ (SEQ ID NO: 3515)5′-AAUUGUUAAACCUGGAACAUGACat-3′ (SEQ ID NO: 2992)3′-CUUUAACAAUUUGGACCUUGUACUGUA-5′ (SEQ ID NO: 2468) HIF-1α-3470 Target:5′-GAAATTGTTAAACCTGGAACATGACAT-3′ (SEQ ID NO: 3516)5′-AUUGUUAAACCUGGAACAUGACAtt-3′ (SEQ ID NO: 2993)3′-UUUAACAAUUUGGACCUUGUACUGUAA-5′ (SEQ ID NO: 2469) HIF-1α-3471 Target:5′-AAATTGTTAAACCTGGAACATGACATT-3′ (SEQ ID NO: 3517)5′-CUGGAACAUGACAUUGUUAAUCAta-3′ (SEQ ID NO: 2994)3′-UGGACCUUGUACUGUAACAAUUAGUAU-5′ (SEQ ID NO: 2470) HIF-1α-3481 Target:5′-ACCTGGAACATGACATTGTTAATCATA-3′ (SEQ ID NO: 3518)5′-CAUGACAUUGUUAAUCAUAUAAUaa-3′ (SEQ ID NO: 2995)3′-UUGUACUGUAACAAUUAGUAUAUUAUU-5′ (SEQ ID NO: 2471) HIF-1α-3487 Target:5′-AACATGACATTGTTAATCATATAATAA-3′ (SEQ ID NO: 3519)5′-AUGACAUUGUUAAUCAUAUAAUAat-3′ (SEQ ID NO: 2996)3′-UGUACUGUAACAAUUAGUAUAUUAUUA-5′ (SEQ ID NO: 2472) HIF-1α-3488 Target:5′-ACATGACATTGTTAATCATATAATAAT-3′ (SEQ ID NO: 3520)5′-CAUUGUUAAUCAUAUAAUAAUGAtt-3′ (SEQ ID NO: 2997)3′-CUGUAACAAUUAGUAUAUUAUUACUAA-5′ (SEQ ID NO: 2473) HIF-1α-3492 Target:5′-GACATTGTTAATCATATAATAATGATT-3′ (SEQ ID NO: 3521)5′-UUGUUAAUCAUAUAAUAAUGAUUct-3′ (SEQ ID NO: 2998)3′-GUAACAAUUAGUAUAUUAUUACUAAGA-5′ (SEQ ID NO: 2474) HIF-1α-3494 Target:5′-CATTGTTAATCATATAATAATGATTCT-3′ (SEQ ID NO: 3522)5′-UGUUAAUCAUAUAAUAAUGAUUCtt-3′ (SEQ ID NO: 2999)3′-UAACAAUUAGUAUAUUAUUACUAAGAA-5′ (SEQ ID NO: 2475) HIF-1α-3495 Target:5′-ATTGTTAATCATATAATAATGATTCTT-3′ (SEQ ID NO: 3523)5′-GUUAAUCAUAUAAUAAUGAUUCUta-3′ (SEQ ID NO: 3000)3′-AACAAUUAGUAUAUUAUUACUAAGAAU-5′ (SEQ ID NO: 2476) HIF-1α-3496 Target:5′-TTGTTAATCATATAATAATGATTCTTA-3′ (SEQ ID NO: 3524)5′-AUAUAAUAAUGAUUCUUAAAUGCtg-3′ (SEQ ID NO: 3001)3′-AGUAUAUUAUUACUAAGAAUUUACGAC-5′ (SEQ ID NO: 2477) HIF-1α-3503 Target:5′-TCATATAATAATGATTCTTAAATGCTG-3′ (SEQ ID NO: 3525)5′-UAUAAUAAUGAUUCUUAAAUGCUgt-3′ (SEQ ID NO: 3002)3′-GUAUAUUAUUACUAAGAAUUUACGACA-5′ (SEQ ID NO: 2478) HIF-1α-3504 Target:5′-CATATAATAATGATTCTTAAATGCTGT-3′ (SEQ ID NO: 3526)5′-AUAAUGAUUCUUAAAUGCUGUAUgg-3′ (SEQ ID NO: 3003)3′-AUUAUUACUAAGAAUUUACGACAUACC-5′ (SEQ ID NO: 2479) HIF-1α-3508 Target:5′-TAATAATGATTCTTAAATGCTGTATGG-3′ (SEQ ID NO: 3527)5′-AUGAUUCUUAAAUGCUGUAUGGUtt-3′ (SEQ ID NO: 3004)3′-AUUACUAAGAAUUUACGACAUACCAAA-5′ (SEQ ID NO: 2480) HIF-1α-3511 Target:5′-TAATGATTCTTAAATGCTGTATGGTTT-3′ (SEQ ID NO: 3528)5′-UGAUUCUUAAAUGCUGUAUGGUUta-3′ (SEQ ID NO: 3005)3′-UUACUAAGAAUUUACGACAUACCAAAU-5′ (SEQ ID NO: 2481) HIF-1α-3512 Target:5′-AATGATTCTTAAATGCTGTATGGTTTA-3′ (SEQ ID NO: 3529)5′-GAUUCUUAAAUGCUGUAUGGUUUat-3′ (SEQ ID NO: 3006)3′-UACUAAGAAUUUACGACAUACCAAAUA-5′ (SEQ ID NO: 2482) HIF-1α-3513 Target:5′-ATGATTCTTAAATGCTGTATGGTTTAT-3′ (SEQ ID NO: 3530)5′-UUAAAUGCUGUAUGGUUUAUUAUtt-3′ (SEQ ID NO: 3007)3′-AGAAUUUACGACAUACCAAAUAAUAAA-5′ (SEQ ID NO: 2483) HIF-1α-3518 Target:5′-TCTTAAATGCTGTATGGTTTATTATTT-3′ (SEQ ID NO: 3531)5′-UAAAUGCUGUAUGGUUUAUUAUUta-3′ (SEQ ID NO: 3008)3′-GAAUUUACGACAUACCAAAUAAUAAAU-5′ (SEQ ID NO: 2484) HIF-1α-3519 Target:5′-CTTAAATGCTGTATGGTTTATTATTTA-3′ (SEQ ID NO: 3532)5′-AAUGCUGUAUGGUUUAUUAUUUAaa-3′ (SEQ ID NO: 3009)3′-AUUUACGACAUACCAAAUAAUAAAUUU-5′ (SEQ ID NO: 2485) HIF-1α-3521 Target:5′-TAAATGCTGTATGGTTTATTATTTAAA-3′ (SEQ ID NO: 3533)5′-UAUGGUUUAUUAUUUAAAUGGGUaa-3′ (SEQ ID NO: 3010)3′-ACAUACCAAAUAAUAAAUUUACCCAUU-5′ (SEQ ID NO: 2486) HIF-1α-3528 Target:5′-TGTATGGTTTATTATTTAAATGGGTAA-3′ (SEQ ID NO: 3534)5′-UGGUUUAUUAUUUAAAUGGGUAAag-3′ (SEQ ID NO: 3011)3′-AUACCAAAUAAUAAAUUUACCCAUUUC-5′ (SEQ ID NO: 2487) HIF-1α-3530 Target:5′-TATGGTTTATTATTTAAATGGGTAAAG-3′ (SEQ ID NO: 3535)5′-GGUUUAUUAUUUAAAUGGGUAAAgc-3′ (SEQ ID NO: 3012)3′-UACCAAAUAAUAAAUUUACCCAUUUCG-5′ (SEQ ID NO: 2488) HIF-1α-3531 Target:5′-ATGGTTTATTATTTAAATGGGTAAAGC-3′ (SEQ ID NO: 3536)5′-UUUAUUAUUUAAAUGGGUAAAGCca-3′ (SEQ ID NO: 3013)3′-CCAAAUAAUAAAUUUACCCAUUUCGGU-5′ (SEQ ID NO: 2489) HIF-1α-3533 Target:5′-GGTTTATTATTTAAATGGGTAAAGCCA-3′ (SEQ ID NO: 3537)5′-UUAUUAUUUAAAUGGGUAAAGCCat-3′ (SEQ ID NO: 3014)3′-CAAAUAAUAAAUUUACCCAUUUCGGUA-5′ (SEQ ID NO: 2490) HIF-1α-3534 Target:5′-GTTTATTATTTAAATGGGTAAAGCCAT-3′ (SEQ ID NO: 3538)5′-AUUUAAAUGGGUAAAGCCAUUUAca-3′ (SEQ ID NO: 3015)3′-AAUAAAUUUACCCAUUUCGGUAAAUGU-5′ (SEQ ID NO: 2491) HIF-1α-3539 Target:5′-TTATTTAAATGGGTAAAGCCATTTACA-3′ (SEQ ID NO: 3539)5′-AUGGGUAAAGCCAUUUACAUAAUat-3′ (SEQ ID NO: 3016)3′-UUUACCCAUUUCGGUAAAUGUAUUAUA-5′ (SEQ ID NO: 2492) HIF-1α-3545 Target:5′-AAATGGGTAAAGCCATTTACATAATAT-3′ (SEQ ID NO: 3540)5′-GGUAAAGCCAUUUACAUAAUAUAga-3′ (SEQ ID NO: 3017)3′-ACCCAUUUCGGUAAAUGUAUUAUAUCU-5′ (SEQ ID NO: 2493) HIF-1α-3548 Target:5′-TGGGTAAAGCCATTTACATAATATAGA-3′ (SEQ ID NO: 3541)5′-UAAAGCCAUUUACAUAAUAUAGAaa-3′ (SEQ ID NO: 3018)3′-CCAUUUCGGUAAAUGUAUUAUAUCUUU-5′ (SEQ ID NO: 2494) HIF-1α-3550 Target:5′-GGTAAAGCCATTTACATAATATAGAAA-3′ (SEQ ID NO: 3542)5′-AAAGCCAUUUACAUAAUAUAGAAag-3′ (SEQ ID NO: 3019)3′-CAUUUCGGUAAAUGUAUUAUAUCUUUC-5′ (SEQ ID NO: 2495) HIF-1α-3551 Target:5′-GTAAAGCCATTTACATAATATAGAAAG-3′ (SEQ ID NO: 3543)5′-CAUUUACAUAAUAUAGAAAGAUAtg-3′ (SEQ ID NO: 3020)3′-CGGUAAAUGUAUUAUAUCUUUCUAUAC-5′ (SEQ ID NO: 2496) HIF-1α-3556 Target:5′-GCCATTTACATAATATAGAAAGATATG-3′ (SEQ ID NO: 3544)5′-AAUAUAGAAAGAUAUGCAUAUAUct-3′ (SEQ ID NO: 3021)3′-UAUUAUAUCUUUCUAUACGUAUAUAGA-5′ (SEQ ID NO: 2497) HIF-1α-3565 Target:5′-ATAATATAGAAAGATATGCATATATCT-3′ (SEQ ID NO: 3545)5′-AUAUAGAAAGAUAUGCAUAUAUCta-3′ (SEQ ID NO: 3022)3′-AUUAUAUCUUUCUAUACGUAUAUAGAU-5′ (SEQ ID NO: 2498) HIF-1α-3566 Target:5′-TAATATAGAAAGATATGCATATATCTA-3′ (SEQ ID NO: 3546)5′-UAUAGAAAGAUAUGCAUAUAUCUag-3′ (SEQ ID NO: 3023)3′-UUAUAUCUUUCUAUACGUAUAUAGAUC-5′ (SEQ ID NO: 2499) HIF-1α-3567 Target:5′-AATATAGAAAGATATGCATATATCTAG-3′ (SEQ ID NO: 3547)5′-GAAAGAUAUGCAUAUAUCUAGAAgg-3′ (SEQ ID NO: 3024)3′-AUCUUUCUAUACGUAUAUAGAUCUUCC-5′ (SEQ ID NO: 2500) HIF-1α-3571 Target:5′-TAGAAAGATATGCATATATCTAGAAGG-3′ (SEQ ID NO: 3548)5′-AGAUAUGCAUAUAUCUAGAAGGUat-3′ (SEQ ID NO: 3025)3′-UUUCUAUACGUAUAUAGAUCUUCCAUA-5′ (SEQ ID NO: 2501) HIF-1α-3574 Target:5′-AAAGATATGCATATATCTAGAAGGTAT-3′ (SEQ ID NO: 3549)5′-GAUAUGCAUAUAUCUAGAAGGUAtg-3′ (SEQ ID NO: 3026)3′-UUCUAUACGUAUAUAGAUCUUCCAUAC-5′ (SEQ ID NO: 2502) HIF-1α-3575 Target:5′-AAGATATGCATATATCTAGAAGGTATG-3′ (SEQ ID NO: 3550)5′-AUAUGCAUAUAUCUAGAAGGUAUgt-3′ (SEQ ID NO: 3027)3′-UCUAUACGUAUAUAGAUCUUCCAUACA-5′ (SEQ ID NO: 2503) HIF-1α-3576 Target:5′-AGATATGCATATATCTAGAAGGTATGT-3′ (SEQ ID NO: 3551)5′-CAUAUAUCUAGAAGGUAUGUGGCat-3′ (SEQ ID NO: 3028)3′-ACGUAUAUAGAUCUUCCAUACACCGUA-5′ (SEQ ID NO: 2504) HIF-1α-3581 Target:5′-TGCATATATCTAGAAGGTATGTGGCAT-3′ (SEQ ID NO: 3552)5′-AUAUAUCUAGAAGGUAUGUGGCAtt-3′ (SEQ ID NO: 3029)3′-CGUAUAUAGAUCUUCCAUACACCGUAA-5′ (SEQ ID NO: 2505) HIF-1α-3582 Target:5′-GCATATATCTAGAAGGTATGTGGCATT-3′ (SEQ ID NO: 3553)5′-UAGAAGGUAUGUGGCAUUUAUUUgg-3′ (SEQ ID NO: 3030)3′-AGAUCUUCCAUACACCGUAAAUAAACC-5′ (SEQ ID NO: 2506) HIF-1α-3589 Target:5′-TCTAGAAGGTATGTGGCATTTATTTGG-3′ (SEQ ID NO: 3554)5′-AGGUAUGUGGCAUUUAUUUGGAUaa-3′ (SEQ ID NO: 3031)3′-CUUCCAUACACCGUAAAUAAACCUAUU-5′ (SEQ ID NO: 2507) HIF-1α-3593 Target:5′-GAAGGTATGTGGCATTTATTTGGATAA-3′ (SEQ ID NO: 3555)5′-AUGUGGCAUUUAUUUGGAUAAAAtt-3′ (SEQ ID NO: 3032)3′-CAUACACCGUAAAUAAACCUAUUUUAA-5′ (SEQ ID NO: 2508) HIF-1α-3597 Target:5′-GTATGTGGCATTTATTTGGATAAAATT-3′ (SEQ ID NO: 3556)5′-GUGGCAUUUAUUUGGAUAAAAUUct-3′ (SEQ ID NO: 3033)3′-UACACCGUAAAUAAACCUAUUUUAAGA-5′ (SEQ ID NO: 2509) HIF-1α-3599 Target:5′-ATGTGGCATTTATTTGGATAAAATTCT-3′ (SEQ ID NO: 3557)5′-UAUUUGGAUAAAAUUCUCAAUUCag-3′ (SEQ ID NO: 3034)3′-AAAUAAACCUAUUUUAAGAGUUAAGUC-5′ (SEQ ID NO: 2510) HIF-1α-3607 Target:5′-TTTATTTGGATAAAATTCTCAATTCAG-3′ (SEQ ID NO: 3558)5′-GAUAAAAUUCUCAAUUCAGAGAAat-3′ (SEQ ID NO: 3035)3′-ACCUAUUUUAAGAGUUAAGUCUCUUUA-5′ (SEQ ID NO: 2511) HIF-1α-3613 Target:5′-TGGATAAAATTCTCAATTCAGAGAAAT-3′ (SEQ ID NO: 3559)5′-UAAAAUUCUCAAUUCAGAGAAAUca-3′ (SEQ ID NO: 3036)3′-CUAUUUUAAGAGUUAAGUCUCUUUAGU-5′ (SEQ ID NO: 2512) HIF-1α-3615 Target:5′-GATAAAATTCTCAATTCAGAGAAATCA-3′ (SEQ ID NO: 3560)5′-AAAUUCUCAAUUCAGAGAAAUCAtc-3′ (SEQ ID NO: 3037)3′-AUUUUAAGAGUUAAGUCUCUUUAGUAG-5′ (SEQ ID NO: 2513) HIF-1α-3617 Target:5′-TAAAATTCTCAATTCAGAGAAATCATC-3′ (SEQ ID NO: 3561)5′-AAUUCAGAGAAAUCAUCUGAUGUtt-3′ (SEQ ID NO: 3038)3′-AGUUAAGUCUCUUUAGUAGACUACAAA-5′ (SEQ ID NO: 2514) HIF-1α-3625 Target:5′-TCAATTCAGAGAAATCATCTGATGTTT-3′ (SEQ ID NO: 3562)5′-CAGAGAAAUCAUCUGAUGUUUCUat-3′ (SEQ ID NO: 3039)3′-AAGUCUCUUUAGUAGACUACAAAGAUA-5′ (SEQ ID NO: 2515) HIF-1α-3629 Target:5′-TTCAGAGAAATCATCTGATGTTTCTAT-3′ (SEQ ID NO: 3563)5′-AAAUCAUCUGAUGUUUCUAUAGUca-3′ (SEQ ID NO: 3040)3′-UCUUUAGUAGACUACAAAGAUAUCAGU-5′ (SEQ ID NO: 2516) HIF-1α-3634 Target:5′-AGAAATCATCTGATGTTTCTATAGTCA-3′ (SEQ ID NO: 3564)5′-UGAUGUUUCUAUAGUCACUUUGCca-3′ (SEQ ID NO: 3041)3′-AGACUACAAAGAUAUCAGUGAAACGGU-5′ (SEQ ID NO: 2517) HIF-1α-3642 Target:5′-TCTGATGTTTCTATAGTCACTTTGCCA-3′ (SEQ ID NO: 3565)5′-GAUGUUUCUAUAGUCACUUUGCCag-3′ (SEQ ID NO: 3042)3′-GACUACAAAGAUAUCAGUGAAACGGUC-5′ (SEQ ID NO: 2518) HIF-1α-3643 Target:5′-CTGATGTTTCTATAGTCACTTTGCCAG-3′ (SEQ ID NO: 3566)5′-AAAAGAAAACAAUACCCUAUGUAgt-3′ (SEQ ID NO: 3043)3′-AGUUUUCUUUUGUUAUGGGAUACAUCA-5′ (SEQ ID NO: 2519) HIF-1α-3671 Target:5′-TCAAAAGAAAACAATACCCTATGTAGT-3′ (SEQ ID NO: 3567)5′-AAGAAAACAAUACCCUAUGUAGUtg-3′ (SEQ ID NO: 3044)3′-UUUUCUUUUGUUAUGGGAUACAUCAAC-5′ (SEQ ID NO: 2520) HIF-1α-3673 Target:5′-AAAAGAAAACAATACCCTATGTAGTTG-3′ (SEQ ID NO: 3568)5′-AGAAAACAAUACCCUAUGUAGUUgt-3′ (SEQ ID NO: 3045)3′-UUUCUUUUGUUAUGGGAUACAUCAACA-5′ (SEQ ID NO: 2521) HIF-1α-3674 Target:5′-AAAGAAAACAATACCCTATGTAGTTGT-3′ (SEQ ID NO: 3569)5′-AAAACAAUACCCUAUGUAGUUGUgg-3′ (SEQ ID NO: 3046)3′-UCUUUUGUUAUGGGAUACAUCAACACC-5′ (SEQ ID NO: 2522) HIF-1α-3676 Target:5′-AGAAAACAATACCCTATGTAGTTGTGG-3′ (SEQ ID NO: 3570)5′-CAAUACCCUAUGUAGUUGUGGAAgt-3′ (SEQ ID NO: 3047)3′-UUGUUAUGGGAUACAUCAACACCUUCA-5′ (SEQ ID NO: 2523) HIF-1α-3680 Target:5′-AACAATACCCTATGTAGTTGTGGAAGT-3′ (SEQ ID NO: 3571)5′-UAUGUAGUUGUGGAAGUUUAUGCta-3′ (SEQ ID NO: 3048)3′-GGAUACAUCAACACCUUCAAAUACGAU-5′ (SEQ ID NO: 2524) HIF-1α-3688 Target:5′-CCTATGTAGTTGTGGAAGTTTATGCTA-3′ (SEQ ID NO: 3572)5′-AUGUAGUUGUGGAAGUUUAUGCUaa-3′ (SEQ ID NO: 3049)3′-GAUACAUCAACACCUUCAAAUACGAUU-5′ (SEQ ID NO: 2525) HIF-1α-3689 Target:5′-CTATGTAGTTGTGGAAGTTTATGCTAA-3′ (SEQ ID NO: 3573)5′-GUUGUGGAAGUUUAUGCUAAUAUtg-3′ (SEQ ID NO: 3050)3′-AUCAACACCUUCAAAUACGAUUAUAAC-5′ (SEQ ID NO: 2526) HIF-1α-3694 Target:5′-TAGTTGTGGAAGTTTATGCTAATATTG-3′ (SEQ ID NO: 3574)5′-UUGUGGAAGUUUAUGCUAAUAUUgt-3′ (SEQ ID NO: 3051)3′-UCAACACCUUCAAAUACGAUUAUAACA-5′ (SEQ ID NO: 2527) HIF-1α-3695 Target:5′-AGTTGTGGAAGTTTATGCTAATATTGT-3′ (SEQ ID NO: 3575)5′-GUGGAAGUUUAUGCUAAUAUUGUgt-3′ (SEQ ID NO: 3052)3′-AACACCUUCAAAUACGAUUAUAACACA-5′ (SEQ ID NO: 2528) HIF-1α-3697 Target:5′-TTGTGGAAGTTTATGCTAATATTGTGT-3′ (SEQ ID NO: 3576)5′-GGAAGUUUAUGCUAAUAUUGUGUaa-3′ (SEQ ID NO: 3053)3′-CACCUUCAAAUACGAUUAUAACACAUU-5′ (SEQ ID NO: 2529) HIF-1α-3699 Target:5′-GTGGAAGTTTATGCTAATATTGTGTAA-3′ (SEQ ID NO: 3577)5′-GAAGUUUAUGCUAAUAUUGUGUAac-3′ (SEQ ID NO: 3054)3′-ACCUUCAAAUACGAUUAUAACACAUUG-5′ (SEQ ID NO: 2530) HIF-1α-3700 Target:5′-TGGAAGTTTATGCTAATATTGTGTAAC-3′ (SEQ ID NO: 3578)5′-AAGUUUAUGCUAAUAUUGUGUAAct-3′ (SEQ ID NO: 3055)3′-CCUUCAAAUACGAUUAUAACACAUUGA-5′ (SEQ ID NO: 2531) HIF-1α-3701 Target:5′-GGAAGTTTATGCTAATATTGTGTAACT-3′ (SEQ ID NO: 3579)5′-GUUUAUGCUAAUAUUGUGUAACUga-3′ (SEQ ID NO: 3056)3′-UUCAAAUACGAUUAUAACACAUUGACU-5′ (SEQ ID NO: 2532) HIF-1α-3703 Target:5′-AAGTTTATGCTAATATTGTGTAACTGA-3′ (SEQ ID NO: 3580)5′-CUAAUAUUGUGUAACUGAUAUUAaa-3′ (SEQ ID NO: 3057)3′-ACGAUUAUAACACAUUGACUAUAAUUU-5′ (SEQ ID NO: 2533) HIF-1α-3710 Target:5′-TGCTAATATTGTGTAACTGATATTAAA-3′ (SEQ ID NO: 3581)5′-AAUAUUGUGUAACUGAUAUUAAAcc-3′ (SEQ ID NO: 3058)3′-GAUUAUAACACAUUGACUAUAAUUUGG-5′ (SEQ ID NO: 2534) HIF-1α-3712 Target:5′-CTAATATTGTGTAACTGATATTAAACC-3′ (SEQ ID NO: 3582)5′-UAUUGUGUAACUGAUAUUAAACCta-3′ (SEQ ID NO: 3059)3′-UUAUAACACAUUGACUAUAAUUUGGAU-5′ (SEQ ID NO: 2535) HIF-1α-3714 Target:5′-AATATTGTGTAACTGATATTAAACCTA-3′ (SEQ ID NO: 3583)5′-CUGAUAUUAAACCUAAAUGUUCUgc-3′ (SEQ ID NO: 3060)3′-UUGACUAUAAUUUGGAUUUACAAGACG-5′ (SEQ ID NO: 2536) HIF-1α-3724 Target:5′-AACTGATATTAAACCTAAATGTTCTGC-3′ (SEQ ID NO: 3584)5′-GUUGGUAUAAAGAUAUUUUGAGCag-3′ (SEQ ID NO: 3061)3′-GACAACCAUAUUUCUAUAAAACUCGUC-5′ (SEQ ID NO: 2537) HIF-1α-3756 Target:5′-CTGTTGGTATAAAGATATTTTGAGCAG-3′ (SEQ ID NO: 3585)5′-UAUAAAGAUAUUUUGAGCAGACUgt-3′ (SEQ ID NO: 3062)3′-CCAUAUUUCUAUAAAACUCGUCUGACA-5′ (SEQ ID NO: 2538) HIF-1α-3761 Target:5′-GGTATAAAGATATTTTGAGCAGACTGT-3′ (SEQ ID NO: 3586)5′-AAGAUAUUUUGAGCAGACUGUAAac-3′ (SEQ ID NO: 3063)3′-AUUUCUAUAAAACUCGUCUGACAUUUG-5′ (SEQ ID NO: 2539) HIF-1α-3765 Target:5′-TAAAGATATTTTGAGCAGACTGTAAAC-3′ (SEQ ID NO: 3587)5′-AGAUAUUUUGAGCAGACUGUAAAca-3′ (SEQ ID NO: 3064)3′-UUUCUAUAAAACUCGUCUGACAUUUGU-5′ (SEQ ID NO: 2540) HIF-1α-3766 Target:5′-AAAGATATTTTGAGCAGACTGTAAACA-3′ (SEQ ID NO: 3588)5′-GAUAUUUUGAGCAGACUGUAAACaa-3′ (SEQ ID NO: 3065)3′-UUCUAUAAAACUCGUCUGACAUUUGUU-5′ (SEQ ID NO: 2541) HIF-1α-3767 Target:5′-AAGATATTTTGAGCAGACTGTAAACAA-3′ (SEQ ID NO: 3589)5′-UUUGAGCAGACUGUAAACAAGAAaa-3′ (SEQ ID NO: 3066)3′-UAAAACUCGUCUGACAUUUGUUCUUUU-5′ (SEQ ID NO: 2542) HIF-1α-3772 Target:5′-ATTTTGAGCAGACTGTAAACAAGAAAA-3′ (SEQ ID NO: 3590)5′-UGAGCAGACUGUAAACAAGAAAAaa-3′ (SEQ ID NO: 3067)3′-AAACUCGUCUGACAUUUGUUCUUUUUU-5′ (SEQ ID NO: 2543) HIF-1α-3774 Target:5′-TTTGAGCAGACTGTAAACAAGAAAAAA-3′ (SEQ ID NO: 3591)5′-CAGACUGUAAACAAGAAAAAAAAaa-3′ (SEQ ID NO: 3068)3′-UCGUCUGACAUUUGUUCUUUUUUUUUU-5′ (SEQ ID NO: 2544) HIF-1α-3778 Target:5′-AGCAGACTGTAAACAAGAAAAAAAAAA-3′ (SEQ ID NO: 3592)5′-CUGUAAACAAGAAAAAAAAAAUCat-3′ (SEQ ID NO: 3069)3′-CUGACAUUUGUUCUUUUUUUUUUAGUA-5′ (SEQ ID NO: 2545) HIF-1α-3782 Target:5′-GACTGTAAACAAGAAAAAAAAAATCAT-3′ (SEQ ID NO: 3593)5′-UGUAAACAAGAAAAAAAAAAUCAtg-3′ (SEQ ID NO: 3070)3′-UGACAUUUGUUCUUUUUUUUUUAGUAC-5′ (SEQ ID NO: 2546) HIF-1α-3783 Target:5′-ACTGTAAACAAGAAAAAAAAAATCATG-3′ (SEQ ID NO: 3594)5′-AAAAAAAAUCAUGCAUUCUUAGCaa-3′ (SEQ ID NO: 3071)3′-UUUUUUUUUUAGUACGUAAGAAUCGUU-5′ (SEQ ID NO: 2547) HIF-1α-3795 Target:5′-AAAAAAAAAATCATGCATTCTTAGCAA-3′ (SEQ ID NO: 3595)5′-AAAAAAAUCAUGCAUUCUUAGCAaa-3′ (SEQ ID NO: 3072)3′-UUUUUUUUUAGUACGUAAGAAUCGUUU-5′ (SEQ ID NO: 2548) HIF-1α-3796 Target:5′-AAAAAAAAATCATGCATTCTTAGCAAA-3′ (SEQ ID NO: 3596)5′-CAUGCAUUCUUAGCAAAAUUGCCta-3′ (SEQ ID NO: 3073)3′-UAGUACGUAAGAAUCGUUUUAACGGAU-5′ (SEQ ID NO: 2549) HIF-1α-3804 Target:5′-ATCATGCATTCTTAGCAAAATTGCCTA-3′ (SEQ ID NO: 3597)5′-CUUAGCAAAAUUGCCUAGUAUGUta-3′ (SEQ ID NO: 3074)3′-AAGAAUCGUUUUAACGGAUCAUACAAU-5′ (SEQ ID NO: 2550) HIF-1α-3812 Target:5′-TTCTTAGCAAAATTGCCTAGTATGTTA-3′ (SEQ ID NO: 3598)5′-UUAGCAAAAUUGCCUAGUAUGUUaa-3′ (SEQ ID NO: 3075)3′-AGAAUCGUUUUAACGGAUCAUACAAUU-5′ (SEQ ID NO: 2551) HIF-1α-3813 Target:5′-TCTTAGCAAAATTGCCTAGTATGTTAA-3′ (SEQ ID NO: 3599)5′-AAAAUUGCCUAGUAUGUUAAUUUgc-3′ (SEQ ID NO: 3076)3′-CGUUUUAACGGAUCAUACAAUUAAACG-5′ (SEQ ID NO: 2552) HIF-1α-3818 Target:5′-GCAAAATTGCCTAGTATGTTAATTTGC-3′ (SEQ ID NO: 3600)5′-AAUUGCCUAGUAUGUUAAUUUGCtc-3′ (SEQ ID NO: 3077)3′-UUUUAACGGAUCAUACAAUUAAACGAG-5′ (SEQ ID NO: 2553) HIF-1α-3820 Target:5′-AAAATTGCCTAGTATGTTAATTTGCTC-3′ (SEQ ID NO: 3601)5′-AUUGCCUAGUAUGUUAAUUUGCUca-3′ (SEQ ID NO: 3078)3′-UUUAACGGAUCAUACAAUUAAACGAGU-5′ (SEQ ID NO: 2554) HIF-1α-3821 Target:5′-AAATTGCCTAGTATGTTAATTTGCTCA-3′ (SEQ ID NO: 3602)5′-UAGUAUGUUAAUUUGCUCAAAAUac-3′ (SEQ ID NO: 3079)3′-GGAUCAUACAAUUAAACGAGUUUUAUG-5′ (SEQ ID NO: 2555) HIF-1α-3827 Target:5′-CCTAGTATGTTAATTTGCTCAAAATAC-3′ (SEQ ID NO: 3603)5′-AGUAUGUUAAUUUGCUCAAAAUAca-3′ (SEQ ID NO: 3080)3′-GAUCAUACAAUUAAACGAGUUUUAUGU-5′ (SEQ ID NO: 2556) HIF-1α-3828 Target:5′-CTAGTATGTTAATTTGCTCAAAATACA-3′ (SEQ ID NO: 3604)5′-GUAUGUUAAUUUGCUCAAAAUACaa-3′ (SEQ ID NO: 3081)3′-AUCAUACAAUUAAACGAGUUUUAUGUU-5′ (SEQ ID NO: 2557) HIF-1α-3829 Target:5′-TAGTATGTTAATTTGCTCAAAATACAA-3′ (SEQ ID NO: 3605)5′-UAAUUUGCUCAAAAUACAAUGUUtg-3′ (SEQ ID NO: 3082)3′-CAAUUAAACGAGUUUUAUGUUACAAAC-5′ (SEQ ID NO: 2558) HIF-1α-3835 Target:5′-GTTAATTTGCTCAAAATACAATGTTTG-3′ (SEQ ID NO: 3606)5′-AAUUUGCUCAAAAUACAAUGUUUga-3′ (SEQ ID NO: 3083)3′-AAUUAAACGAGUUUUAUGUUACAAACU-5′ (SEQ ID NO: 2559) HIF-1α-3836 Target:5′-TTAATTTGCTCAAAATACAATGTTTGA-3′ (SEQ ID NO: 3607)5′-UUUGCUCAAAAUACAAUGUUUGAtt-3′ (SEQ ID NO: 3084)3′-UUAAACGAGUUUUAUGUUACAAACUAA-5′ (SEQ ID NO: 2560) HIF-1α-3838 Target:5′-AATTTGCTCAAAATACAATGTTTGATT-3′ (SEQ ID NO: 3608)5′-CAAAAUACAAUGUUUGAUUUUAUgc-3′ (SEQ ID NO: 3085)3′-GAGUUUUAUGUUACAAACUAAAAUACG-5′ (SEQ ID NO: 2561) HIF-1α-3844 Target:5′-CTCAAAATACAATGTTTGATTTTATGC-3′ (SEQ ID NO: 3609)5′-AAAUACAAUGUUUGAUUUUAUGCac-3′ (SEQ ID NO: 3086)3′-GUUUUAUGUUACAAACUAAAAUACGUG-5′ (SEQ ID NO: 2562) HIF-1α-3846 Target:5′-CAAAATACAATGTTTGATTTTATGCAC-3′ (SEQ ID NO: 3610)5′-AAUACAAUGUUUGAUUUUAUGCAct-3′ (SEQ ID NO: 3087)3′-UUUUAUGUUACAAACUAAAAUACGUGA-5′ (SEQ ID NO: 2563) HIF-1α-3847 Target:5′-AAAATACAATGTTTGATTTTATGCACT-3′ (SEQ ID NO: 3611)5′-AUGUUUGAUUUUAUGCACUUUGUcg-3′ (SEQ ID NO: 3088)3′-GUUACAAACUAAAAUACGUGAAACAGC-5′ (SEQ ID NO: 2564) HIF-1α-3853 Target:5′-CAATGTTTGATTTTATGCACTTTGTCG-3′ (SEQ ID NO: 3612)5′-UGUUUGAUUUUAUGCACUUUGUCgc-3′ (SEQ ID NO: 3089)3′-UUACAAACUAAAAUACGUGAAACAGCG-5′ (SEQ ID NO: 2565) HIF-1α-3854 Target:5′-AATGTTTGATTTTATGCACTTTGTCGC-3′ (SEQ ID NO: 3613)5′-UAUGCACUUUGUCGCUAUUAACAtc-3′ (SEQ ID NO: 3090)3′-AAAUACGUGAAACAGCGAUAAUUGUAG-5′ (SEQ ID NO: 2566) HIF-1α-3864 Target:5′-TTTATGCACTTTGTCGCTATTAACATC-3′ (SEQ ID NO: 3614)5′-UUGUCGCUAUUAACAUCCUUUUUtt-3′ (SEQ ID NO: 3091)3′-GAAACAGCGAUAAUUGUAGGAAAAAAA-5′ (SEQ ID NO: 2567) HIF-1α-3872 Target:5′-CTTTGTCGCTATTAACATCCTTTTTTT-3′ (SEQ ID NO: 3615)5′-UUUUUUCAUGUAGAUUUCAAUAAtt-3′ (SEQ ID NO: 3092)3′-GAAAAAAAGUACAUCUAAAGUUAUUAA-5′ (SEQ ID NO: 2568) HIF-1α-3891 Target:5′-CTTTTTTTCATGTAGATTTCAATAATT-3′ (SEQ ID NO: 3616)5′-UUUUUCAUGUAGAUUUCAAUAAUtg-3′ (SEQ ID NO: 3093)3′-AAAAAAAGUACAUCUAAAGUUAUUAAC-5′ (SEQ ID NO: 2569) HIF-1α-3892 Target:5′-TTTTTTTCATGTAGATTTCAATAATTG-3′ (SEQ ID NO: 3617)5′-CAUGUAGAUUUCAAUAAUUGAGUaa-3′ (SEQ ID NO: 3094)3′-AAGUACAUCUAAAGUUAUUAACUCAUU-5′ (SEQ ID NO: 2570) HIF-1α-3897 Target:5′-TTCATGTAGATTTCAATAATTGAGTAA-3′ (SEQ ID NO: 3618)5′-AUGUAGAUUUCAAUAAUUGAGUAat-3′ (SEQ ID NO: 3095)3′-AGUACAUCUAAAGUUAUUAACUCAUUA-5′ (SEQ ID NO: 2571) HIF-1α-3898 Target:5′-TCATGTAGATTTCAATAATTGAGTAAT-3′ (SEQ ID NO: 3619)5′-UGUAGAUUUCAAUAAUUGAGUAAtt-3′ (SEQ ID NO: 3096)3′-GUACAUCUAAAGUUAUUAACUCAUUAA-5′ (SEQ ID NO: 2572) HIF-1α-3899 Target:5′-CATGTAGATTTCAATAATTGAGTAATT-3′ (SEQ ID NO: 3620)5′-GUAGAUUUCAAUAAUUGAGUAAUtt-3′ (SEQ ID NO: 3097)3′-UACAUCUAAAGUUAUUAACUCAUUAAA-5′ (SEQ ID NO: 2573) HIF-1α-3900 Target:5′-ATGTAGATTTCAATAATTGAGTAATTT-3′ (SEQ ID NO: 3621)5′-UAGAUUUCAAUAAUUGAGUAAUUtt-3′ (SEQ ID NO: 3098)3′-ACAUCUAAAGUUAUUAACUCAUUAAAA-5′ (SEQ ID NO: 2574) HIF-1α-3901 Target:5′-TGTAGATTTCAATAATTGAGTAATTTT-3′ (SEQ ID NO: 3622)5′-AGAUUUCAAUAAUUGAGUAAUUUta-3′ (SEQ ID NO: 3099)3′-CAUCUAAAGUUAUUAACUCAUUAAAAU-5′ (SEQ ID NO: 2575) HIF-1α-3902 Target:5′-GTAGATTTCAATAATTGAGTAATTTTA-3′ (SEQ ID NO: 3623)5′-GAUUUCAAUAAUUGAGUAAUUUUag-3′ (SEQ ID NO: 3100)3′-AUCUAAAGUUAUUAACUCAUUAAAAUC-5′ (SEQ ID NO: 2576) HIF-1α-3903 Target:5′-TAGATTTCAATAATTGAGTAATTTTAG-3′ (SEQ ID NO: 3624)5′-AUUUCAAUAAUUGAGUAAUUUUAga-3′ (SEQ ID NO: 3101)3′-UCUAAAGUUAUUAACUCAUUAAAAUCU-5′ (SEQ ID NO: 2577) HIF-1α-3904 Target:5′-AGATTTCAATAATTGAGTAATTTTAGA-3′ (SEQ ID NO: 3625)5′-AUAAUUGAGUAAUUUUAGAAGCAtt-3′ (SEQ ID NO: 3102)3′-GUUAUUAACUCAUUAAAAUCUUCGUAA-5′ (SEQ ID NO: 2578) HIF-1α-3910 Target:5′-CAATAATTGAGTAATTTTAGAAGCATT-3′ (SEQ ID NO: 3626)5′-UUGAGUAAUUUUAGAAGCAUUAUtt-3′ (SEQ ID NO: 3103)3′-UUAACUCAUUAAAAUCUUCGUAAUAAA-5′ (SEQ ID NO: 2579) HIF-1α-3914 Target:5′-AATTGAGTAATTTTAGAAGCATTATTT-3′ (SEQ ID NO: 3627)5′-UGAGUAAUUUUAGAAGCAUUAUUtt-3′ (SEQ ID NO: 3104)3′-UAACUCAUUAAAAUCUUCGUAAUAAAA-5′ (SEQ ID NO: 2580) HIF-1α-3915 Target:5′-ATTGAGTAATTTTAGAAGCATTATTTT-3′ (SEQ ID NO: 3628)5′-AGUAAUUUUAGAAGCAUUAUUUUag-3′ (SEQ ID NO: 3105)3′-ACUCAUUAAAAUCUUCGUAAUAAAAUC-5′ (SEQ ID NO: 2581) HIF-1α-3917 Target:5′-TGAGTAATTTTAGAAGCATTATTTTAG-3′ (SEQ ID NO: 3629)5′-AUUUUAGAAGCAUUAUUUUAGGAat-3′ (SEQ ID NO: 3106)3′-AUUAAAAUCUUCGUAAUAAAAUCCUUA-5′ (SEQ ID NO: 2582) HIF-1α-3921 Target:5′-TAATTTTAGAAGCATTATTTTAGGAAT-3′ (SEQ ID NO: 3630)5′-UAGAAGCAUUAUUUUAGGAAUAUat-3′ (SEQ ID NO: 3107)3′-AAAUCUUCGUAAUAAAAUCCUUAUAUA-5′ (SEQ ID NO: 2583) HIF-1α-3925 Target:5′-TTTAGAAGCATTATTTTAGGAATATAT-3′ (SEQ ID NO: 3631)5′-GAAGCAUUAUUUUAGGAAUAUAUag-3′ (SEQ ID NO: 3108)3′-AUCUUCGUAAUAAAAUCCUUAUAUAUC-5′ (SEQ ID NO: 2584) HIF-1α-3927 Target:5′-TAGAAGCATTATTTTAGGAATATATAG-3′ (SEQ ID NO: 3632)5′-CAUUAUUUUAGGAAUAUAUAGUUgt-3′ (SEQ ID NO: 3109)3′-UCGUAAUAAAAUCCUUAUAUAUCAACA-5′ (SEQ ID NO: 2585) HIF-1α-3931 Target:5′-AGCATTATTTTAGGAATATATAGTTGT-3′ (SEQ ID NO: 3633)5′-UUAUUUUAGGAAUAUAUAGUUGUca-3′ (SEQ ID NO: 3110)3′-GUAAUAAAAUCCUUAUAUAUCAACAGU-5′ (SEQ ID NO: 2586) HIF-1α-3933 Target:5′-CATTATTTTAGGAATATATAGTTGTCA-3′ (SEQ ID NO: 3634)5′-GGAAUAUAUAGUUGUCACAGUAAat-3′ (SEQ ID NO: 3111)3′-AUCCUUAUAUAUCAACAGUGUCAUUUA-5′ (SEQ ID NO: 2587) HIF-1α-3941 Target:5′-TAGGAATATATAGTTGTCACAGTAAAT-3′ (SEQ ID NO: 3635)5′-GAAUAUAUAGUUGUCACAGUAAAta-3′ (SEQ ID NO: 3112)3′-UCCUUAUAUAUCAACAGUGUCAUUUAU-5′ (SEQ ID NO: 2588) HIF-1α-3942 Target:5′-AGGAATATATAGTTGTCACAGTAAATA-3′ (SEQ ID NO: 3636)5′-AAUAUAUAGUUGUCACAGUAAAUat-3′ (SEQ ID NO: 3113)3′-CCUUAUAUAUCAACAGUGUCAUUUAUA-5′ (SEQ ID NO: 2589) HIF-1α-3943 Target:5′-GGAATATATAGTTGTCACAGTAAATAT-3′ (SEQ ID NO: 3637)5′-UAUAUAGUUGUCACAGUAAAUAUct-3′ (SEQ ID NO: 3114)3′-UUAUAUAUCAACAGUGUCAUUUAUAGA-5′ (SEQ ID NO: 2590) HIF-1α-3945 Target:5′-AATATATAGTTGTCACAGTAAATATCT-3′ (SEQ ID NO: 3638)5′-AUAUAGUUGUCACAGUAAAUAUCtt-3′ (SEQ ID NO: 3115)3′-UAUAUAUCAACAGUGUCAUUUAUAGAA-5′ (SEQ ID NO: 2591) HIF-1α-3946 Target:5′-ATATATAGTTGTCACAGTAAATATCTT-3′ (SEQ ID NO: 3639)5′-GUUGUCACAGUAAAUAUCUUGUUtt-3′ (SEQ ID NO: 3116)3′-AUCAACAGUGUCAUUUAUAGAACAAAA-5′ (SEQ ID NO: 2592) HIF-1α-3951 Target:5′-TAGTTGTCACAGTAAATATCTTGTTTT-3′ (SEQ ID NO: 3640)5′-UUGUCACAGUAAAUAUCUUGUUUtt-3′ (SEQ ID NO: 3117)3′-UCAACAGUGUCAUUUAUAGAACAAAAA-5′ (SEQ ID NO: 2593) HIF-1α-3952 Target:5′-AGTTGTCACAGTAAATATCTTGTTTTT-3′ (SEQ ID NO: 3641)5′-AAAUAUCUUGUUUUUUCUAUGUAca-3′ (SEQ ID NO: 3118)3′-CAUUUAUAGAACAAAAAAGAUACAUGU-5′ (SEQ ID NO: 2594) HIF-1α-3962 Target:5′-GTAAATATCTTGTTTTTTCTATGTACA-3′ (SEQ ID NO: 3642)5′-AAUAUCUUGUUUUUUCUAUGUACat-3′ (SEQ ID NO: 3119)3′-AUUUAUAGAACAAAAAAGAUACAUGUA-5′ (SEQ ID NO: 2595) HIF-1α-3963 Target:5′-TAAATATCTTGTTTTTTCTATGTACAT-3′ (SEQ ID NO: 3643)5′-CUUGUUUUUUCUAUGUACAUUGUac-3′ (SEQ ID NO: 3120)3′-UAGAACAAAAAAGAUACAUGUAACAUG-5′ (SEQ ID NO: 2596) HIF-1α-3968 Target:5′-ATCTTGTTTTTTCTATGTACATTGTAC-3′ (SEQ ID NO: 3644)5′-UUGUUUUUUCUAUGUACAUUGUAca-3′ (SEQ ID NO: 3121)3′-AGAACAAAAAAGAUACAUGUAACAUGU-5′ (SEQ ID NO: 2597) HIF-1α-3969 Target:5′-TCTTGTTTTTTCTATGTACATTGTACA-3′ (SEQ ID NO: 3645)5′-UGUUUUUUCUAUGUACAUUGUACaa-3′ (SEQ ID NO: 3122)3′-GAACAAAAAAGAUACAUGUAACAUGUU-5′ (SEQ ID NO: 2598) HIF-1α-3970 Target:5′-CTTGTTTTTTCTATGTACATTGTACAA-3′ (SEQ ID NO: 3646)5′-GUUUUUUCUAUGUACAUUGUACAaa-3′ (SEQ ID NO: 3123)3′-AACAAAAAAGAUACAUGUAACAUGUUU-5′ (SEQ ID NO: 2599) HIF-1α-3971 Target:5′-TTGTTTTTTCTATGTACATTGTACAAA-3′ (SEQ ID NO: 3647)5′-CUAUGUACAUUGUACAAAUUUUUca-3′ (SEQ ID NO: 3124)3′-AAGAUACAUGUAACAUGUUUAAAAAGU-5′ (SEQ ID NO: 2600) HIF-1α-3978 Target:5′-TTCTATGTACATTGTACAAATTTTTCA-3′ (SEQ ID NO: 3648)5′-UAUGUACAUUGUACAAAUUUUUCat-3′ (SEQ ID NO: 3125)3′-AGAUACAUGUAACAUGUUUAAAAAGUA-5′ (SEQ ID NO: 2601) HIF-1α-3979 Target:5′-TCTATGTACATTGTACAAATTTTTCAT-3′ (SEQ ID NO: 3649)5′-UUUUCAUUCCUUUUGCUCUUUGUgg-3′ (SEQ ID NO: 3126)3′-UAAAAAGUAAGGAAAACGAGAAACACC-5′ (SEQ ID NO: 2602) HIF-1α-3997 Target:5′-ATTTTTCATTCCTTTTGCTCTTTGTGG-3′ (SEQ ID NO: 3650)5′-GUUGGAUCUAACACUAACUGUAUtg-3′ (SEQ ID NO: 3127)3′-ACCAACCUAGAUUGUGAUUGACAUAAC-5′ (SEQ ID NO: 2603) HIF-1α-4021 Target:5′-TGGTTGGATCTAACACTAACTGTATTG-3′ (SEQ ID NO: 3651)5′-UUGGAUCUAACACUAACUGUAUUgt-3′ (SEQ ID NO: 3128)3′-CCAACCUAGAUUGUGAUUGACAUAACA-5′ (SEQ ID NO: 2604) HIF-1α-4022 Target:5′-GGTTGGATCTAACACTAACTGTATTGT-3′ (SEQ ID NO: 3652)5′-GGAUCUAACACUAACUGUAUUGUtt-3′ (SEQ ID NO: 3129)3′-AACCUAGAUUGUGAUUGACAUAACAAA-5′ (SEQ ID NO: 2605) HIF-1α-4024 Target:5′-TTGGATCTAACACTAACTGTATTGTTT-3′ (SEQ ID NO: 3653)5′-GUAUUGUUUUGUUACAUCAAAUAaa-3′ (SEQ ID NO: 3130)3′-GACAUAACAAAACAAUGUAGUUUAUUU-5′ (SEQ ID NO: 2606) HIF-1α-4040 Target:5′-CTGTATTGTTTTGTTACATCAAATAAA-3′ (SEQ ID NO: 3654)5′-UAUUGUUUUGUUACAUCAAAUAAac-3′ (SEQ ID NO: 3131)3′-ACAUAACAAAACAAUGUAGUUUAUUUG-5′ (SEQ ID NO: 2607) HIF-1α-4041 Target:5′-TGTATTGTTTTGTTACATCAAATAAAC-3′ (SEQ ID NO: 3655)5′-AUUGUUUUGUUACAUCAAAUAAAca-3′ (SEQ ID NO: 3132)3′-CAUAACAAAACAAUGUAGUUUAUUUGU-5′ (SEQ ID NO: 2608) HIF-1α-4042 Target:5′-GTATTGTTTTGTTACATCAAATAAACA-3′ (SEQ ID NO: 3656)5′-UGUUUUGUUACAUCAAAUAAACAtc-3′ (SEQ ID NO: 3133)3′-UAACAAAACAAUGUAGUUUAUUUGUAG-5′ (SEQ ID NO: 2609) HIF-1α-4044 Target:5′-ATTGTTTTGTTACATCAAATAAACATC-3′ (SEQ ID NO: 3657)5′-UGUGGACCAGGCAAAAAAAAAAAaa-3′ (SEQ ID NO: 3134)3′-AGACACCUGGUCCGUUUUUUUUUUUUU-5′ (SEQ ID NO: 2610) HIF-1α-4072 Target:5′-TCTGTGGACCAGGCAAAAAAAAAAAAA-3′ (SEQ ID NO: 3658)5′-GUGGACCAGGCAAAAAAAAAAAAaa-3′ (SEQ ID NO: 3135)3′-GACACCUGGUCCGUUUUUUUUUUUUUU-5′ (SEQ ID NO: 2611) HIF-1α-4073 Target:5′-CTGTGGACCAGGCAAAAAAAAAAAAAA-3′ (SEQ ID NO: 3659)5′-CAGGCAAAAAAAAAAAAAAAAAAaa-3′ (SEQ ID NO: 3136)3′-UGGUCCGUUUUUUUUUUUUUUUUUUUU-5′ (SEQ ID NO: 2612) HIF-1α-4079 Target:5′-ACCAGGCAAAAAAAAAAAAAAAAAAAA-3′ (SEQ ID NO: 3660)5′-CUUUUUCAAGCAGUAGGAAUUAUtt-3′ (SEQ ID NO: 3137)3′-GUGAAAAAGUUCGUCAUCCUUAAUAAA-5′ (SEQ ID NO: 2613) HIF-1α-2610t2 Targ:5′-CACTTTTTCAAGCAGTAGGAATTATTT-3′ (SEQ ID NO: 3661)5′-UUUUUCAAGCAGUAGGAAUUAUUta-3′ (SEQ ID NO: 3138)3′-UGAAAAAGUUCGUCAUCCUUAAUAAAU-5′ (SEQ ID NO: 2614) HIF-1α-2611t2 Targ:5′-ACTTTTTCAAGCAGTAGGAATTATTTA-3′ (SEQ ID NO: 3662)5′-CAAGCAGUAGGAAUUAUUUAGCAtg-3′ (SEQ ID NO: 3139)3′-AAGUUCGUCAUCCUUAAUAAAUCGUAC-5′ (SEQ ID NO: 2615) HIF-1α-2616t2 Targ:5′-TTCAAGCAGTAGGAATTATTTAGCATG-3′ (SEQ ID NO: 3663)5′-CAGUAGGAAUUAUUUAGCAUGUAga-3′ (SEQ ID NO: 3140)3′-UCGUCAUCCUUAAUAAAUCGUACAUCU-5′ (SEQ ID NO: 2616) HIF-1α-2620t2 Targ:5′-AGCAGTAGGAATTATTTAGCATGTAGA-3′ (SEQ ID NO: 3664)5′-GUAGGAAUUAUUUAGCAUGUAGAct-3′ (SEQ ID NO: 3141)3′-GUCAUCCUUAAUAAAUCGUACAUCUGA-5′ (SEQ ID NO: 2617) HIF-1α-2622t2 Targ:5′-CAGTAGGAATTATTTAGCATGTAGACT-3′ (SEQ ID NO: 3665)5′-UAGGAAUUAUUUAGCAUGUAGACtg-3′ (SEQ ID NO: 3142)3′-UCAUCCUUAAUAAAUCGUACAUCUGAC-5′ (SEQ ID NO: 2618) HIF-1α-2623t2 Targ:5′-AGTAGGAATTATTTAGCATGTAGACTG-3′ (SEQ ID NO: 3666)5′-AGGAAUUAUUUAGCAUGUAGACUgc-3′ (SEQ ID NO: 3143)3′-CAUCCUUAAUAAAUCGUACAUCUGACG-5′ (SEQ ID NO: 2619) HIF-1α-2624t2 Targ:5′-GTAGGAATTATTTAGCATGTAGACTGC-3′ (SEQ ID NO: 3667)

TABLE 3 Selected Anti-HIF-1α DsiRNAs, Unmodified Duplexes (Asymmetrics,HIF-1α Variant 1) 5′-GAAGACAUCGCGGGGACCGAUUCAC-3′ (SEQ ID NO: 1135)3′-CACUUCUGUAGCGCCCCUGGCUAAGUG-5′ (SEQ ID NO: 27) HIF-1α-403 Target:5′-GTGAAGACATCGCGGGGACCGATTCAC-3′ (SEQ ID NO: 783)5′-GUUCUGAACGUCGAAAAGAAAAGUC-3′ (SEQ ID NO: 1136)3′-UUCAAGACUUGCAGCUUUUCUUUUCAG-5′ (SEQ ID NO: 33) HIF-1α-469 Target:5′-AAGTTCTGAACGTCGAAAAGAAAAGTC-3′ (SEQ ID NO: 789)5′-UGAAGUUUUUUAUGAGCUUGCUCAU-3′ (SEQ ID NO: 1137)3′-AGACUUCAAAAAAUACUCGAACGAGUA-5′ (SEQ ID NO: 39) HIF-1α-530 Target:5′-TCTGAAGTTTTTTATGAGCTTGCTCAT-3′ (SEQ ID NO: 795)5′-GUUUUUUAUGAGCUUGCUCAUCAGU-3′ (SEQ ID NO: 1138)3′-UUCAAAAAAUACUCGAACGAGUAGUCA-5′ (SEQ ID NO: 41) HIF-1α-534 Target:5′-AAGTTTTTTATGAGCTTGCTCATCAGT-3′ (SEQ ID NO: 797)5′-UGAAUUGCUUUUAUUUGAAAGCCUU-3′ (SEQ ID NO: 1139)3′-CUACUUAACGAAAAUAAACUUUCGGAA-5′ (SEQ ID NO: 55) HIF-1α-691 Target:5′-GATGAATTGCTTTTATTTGAAAGCCTT-3′ (SEQ ID NO: 811)5′-GCCUUGGAUGGUUUUGUUAUGGUUC-3′ (SEQ ID NO: 1140)3′-UUCGGAACCUACCAAAACAAUACCAAG-5′ (SEQ ID NO: 57) HIF-1α-711 Target:5′-AAGCCTTGGATGGTTTTGTTATGGTTC-3′ (SEQ ID NO: 813)5′-CUUGGAUGGUUUUGUUAUGGUUCUC-3′ (SEQ ID NO: 1141)3′-CGGAACCUACCAAAACAAUACCAAGAG-5′ (SEQ ID NO: 58) HIF-1α-713 Target:5′-GCCTTGGATGGTTTTGTTATGGTTCTC-3′ (SEQ ID NO: 814)5′-UGGAUGGUUUUGUUAUGGUUCUCAC-3′ (SEQ ID NO: 1142)3′-GAACCUACCAAAACAAUACCAAGAGUG-5′ (SEQ ID NO: 59) HIF-1α-715 Target:5′-CTTGGATGGTTTTGTTATGGTTCTCAC-3′ (SEQ ID NO: 815)5′-GAUGGUUUUGUUAUGGUUCUCACAG-3′ (SEQ ID NO: 1143)3′-ACCUACCAAAACAAUACCAAGAGUGUC-5′ (SEQ ID NO: 60) HIF-1α-717 Target:5′-TGGATGGTTTTGTTATGGTTCTCACAG-3′ (SEQ ID NO: 816)5′-AUUUACAUUUCUGAUAAUGUGAACA-3′ (SEQ ID NO: 1144)3′-ACUAAAUGUAAAGACUAUUACACUUGU-5′ (SEQ ID NO: 61) HIF-1α-756 Target:5′-TGATTTACATTTCTGATAATGTGAACA-3′ (SEQ ID NO: 817)5′-GUUUGAUUUUACUCAUCCAUGUGAC-3′ (SEQ ID NO: 1145)3′-CACAAACUAAAAUGAGUAGGUACACUG-5′ (SEQ ID NO: 64) HIF-1α-824 Target:5′-GTGTTTGATTTTACTCATCCATGTGAC-3′ (SEQ ID NO: 820)5′-AGUAACCAACCUCAGUGUGGGUAUA-3′ (SEQ ID NO: 1146)3′-UGUCAUUGGUUGGAGUCACACCCAUAU-5′ (SEQ ID NO: 88) HIF-1α-1041 Target:5′-ACAGTAACCAACCTCAGTGTGGGTATA-3′ (SEQ ID NO: 844)5′-UGCUGAUUUGUGAACCCAUUCCUCA-3′ (SEQ ID NO: 1147)3′-CCACGACUAAACACUUGGGUAAGGAGU-5′ (SEQ ID NO: 97) HIF-1α-1090 Target:5′-GGTGCTGATTTGTGAACCCATTCCTCA-3′ (SEQ ID NO: 853)5′-UUAUCAUGCUUUGGACUCUGAUCAU-3′ (SEQ ID NO: 1148)3′-AUAAUAGUACGAAACCUGAGACUAGUA-5′ (SEQ ID NO: 118) HIF-1α-1262 Target:5′-TATTATCATGCTTTGGACTCTGATCAT-3′ (SEQ ID NO: 874)5′-UGCUUUGGACUCUGAUCAUCUGACC-3′ (SEQ ID NO: 1149)3′-GUACGAAACCUGAGACUAGUAGACUGG-5′ (SEQ ID NO: 120) HIF-1α-1268 Target:5′-CATGCTTTGGACTCTGATCATCTGACC-3′ (SEQ ID NO: 876)5′-UUUGGACUCUGAUCAUCUGACCAAA-3′ (SEQ ID NO: 1150)3′-CGAAACCUGAGACUAGUAGACUGGUUU-5′ (SEQ ID NO: 121) HIF-1α-1271 Target:5′-GCTTTGGACTCTGATCATCTGACCAAA-3′ (SEQ ID NO: 877)5′-CAGGAUGCUUGCCAAAAGAGGUGGA-3′ (SEQ ID NO: 1151)3′-AUGUCCUACGAACGGUUUUCUCCACCU-5′ (SEQ ID NO: 145) HIF-1α-1343 Target:5′-TACAGGATGCTTGCCAAAAGAGGTGGA-3′ (SEQ ID NO: 901)5′-AUAUGUCUGGGUUGAAACUCAAGCA-3′ (SEQ ID NO: 1152)3′-CCUAUACAGACCCAACUUUGAGUUCGU-5′ (SEQ ID NO: 157) HIF-1α-1367 Target:5′-GGATATGTCTGGGTTGAAACTCAAGCA-3′ (SEQ ID NO: 913)5′-AUGUCUGGGUUGAAACUCAAGCAAC-3′ (SEQ ID NO: 1153)3′-UAUACAGACCCAACUUUGAGUUCGUUG-5′ (SEQ ID NO: 158) HIF-1α-1369 Target:5′-ATATGTCTGGGTTGAAACTCAAGCAAC-3′ (SEQ ID NO: 914)5′-GUUGAAACUCAAGCAACUGUCAUAU-3′ (SEQ ID NO: 1154)3′-CCCAACUUUGAGUUCGUUGACAGUAUA-5′ (SEQ ID NO: 162) HIF-1α-1377 Target:5′-GGGTTGAAACTCAAGCAACTGTCATAT-3′ (SEQ ID NO: 918)5′-UGAAACUCAAGCAACUGUCAUAUAU-3′ (SEQ ID NO: 1155)3′-CAACUUUGAGUUCGUUGACAGUAUAUA-5′ (SEQ ID NO: 163) HIF-1α-1379 Target:5′-GTTGAAACTCAAGCAACTGTCATATAT-3′ (SEQ ID NO: 919)5′-CACGACUUGAUUUUCUCCCUUCAAC-3′ (SEQ ID NO: 1156)3′-UCGUGCUGAACUAAAAGAGGGAAGUUG-5′ (SEQ ID NO: 175) HIF-1α-1470 Target:5′-AGCACGACTTGATTTTCTCCCTTCAAC-3′ (SEQ ID NO: 931)5′-UUGAUUUUCUCCCUUCAACAAACAG-3′ (SEQ ID NO: 1157)3′-UGAACUAAAAGAGGGAAGUUGUUUGUC-5′ (SEQ ID NO: 178) HIF-1α-1476 Target:5′-ACTTGATTTTCTCCCTTCAACAAACAG-3′ (SEQ ID NO: 934)5′-GAUUUUCUCCCUUCAACAAACAGAA-3′ (SEQ ID NO: 1158)3′-AACUAAAAGAGGGAAGUUGUUUGUCUU-5′ (SEQ ID NO: 179) HIF-1α-1478 Target:5′-TTGATTTTCTCCCTTCAACAAACAGAA-3′ (SEQ ID NO: 935)5′-UUCUCCCUUCAACAAACAGAAUGUG-3′ (SEQ ID NO: 1159)3′-AAAAGAGGGAAGUUGUUUGUCUUACAC-5′ (SEQ ID NO: 181) HIF-1α-1482 Target:5′-TTTTCTCCCTTCAACAAACAGAATGTG-3′ (SEQ ID NO: 937)5′-CAAUCAUAUCUUUAGAUUUUGGCAG-3′ (SEQ ID NO: 1160)3′-GUGUUAGUAUAGAAAUCUAAAACCGUC-5′ (SEQ ID NO: 185) HIF-1α-1648 Target:5′-CACAATCATATCTTTAGATTTTGGCAG-3′ (SEQ ID NO: 941)5′-GAAGUUGCAUUAAAAUUAGAACCAA-3′ (SEQ ID NO: 1161)3′-UUCUUCAACGUAAUUUUAAUCUUGGUU-5′ (SEQ ID NO: 194) HIF-1α-1845 Target:5′-AAGAAGTTGCATTAAAATTAGAACCAA-3′ (SEQ ID NO: 950)5′-AAGCACUAGACAAAGUUCACCUGAG-3′ (SEQ ID NO: 1162)3′-CCUUCGUGAUCUGUUUCAAGUGGACUC-5′ (SEQ ID NO: 197) HIF-1α-1940 Target:5′-GGAAGCACTAGACAAAGTTCACCTGAG-3′ (SEQ ID NO: 953)5′-ACUAGACAAAGUUCACCUGAGCCUA-3′ (SEQ ID NO: 1163)3′-CGUGAUCUGUUUCAAGUGGACUCGGAU-5′ (SEQ ID NO: 199) HIF-1α-1944 Target:5′-GCACTAGACAAAGTTCACCTGAGCCTA-3′ (SEQ ID NO: 955)5′-UAGACAAAGUUCACCUGAGCCUAAU-3′ (SEQ ID NO: 1164)3′-UGAUCUGUUUCAAGUGGACUCGGAUUA-5′ (SEQ ID NO: 200) HIF-1α-1946 Target:5′-ACTAGACAAAGTTCACCTGAGCCTAAT-3′ (SEQ ID NO: 956)5′-GUAGAAAAACUUUUUGCUGAAGACA-3′ (SEQ ID NO: 1165)3′-ACCAUCUUUUUGAAAAACGACUUCUGU-5′ (SEQ ID NO: 203) HIF-1α-2034 Target:5′-TGGTAGAAAAACTTTTTGCTGAAGACA-3′ (SEQ ID NO: 959)5′-CAAAAGACAAUUAUUUUAAUACCCU-3′ (SEQ ID NO: 1166)3′-UCGUUUUCUGUUAAUAAAAUUAUGGGA-5′ (SEQ ID NO: 220) HIF-1α-2730 Target:5′-AGCAAAAGACAATTATTTTAATACCCT-3′ (SEQ ID NO: 976)5′-GAUUACCACAGCUGACCAGUUAUGA-3′ (SEQ ID NO: 1167)3′-ACCUAAUGGUGUCGACUGGUCAAUACU-5′ (SEQ ID NO: 223) HIF-1α-2800 Target:5′-TGGATTACCACAGCTGACCAGTTATGA-3′ (SEQ ID NO: 979)5′-CUUUGGAUCAAGUUAACUGAGCUUU-3′ (SEQ ID NO: 1168)3′-UCGAAACCUAGUUCAAUUGACUCGAAA-5′ (SEQ ID NO: 249) HIF-1α-2890 Target:5′-AGCTTTGGATCAAGTTAACTGAGCTTT-3′ (SEQ ID NO: 1005)5′-CAUUCCUUUUUUUGGACACUGGUGG-3′ (SEQ ID NO: 1169)3′-AAGUAAGGAAAAAAACCUGUGACCACC-5′ (SEQ ID NO: 255) HIF-1α-2925 Target:5′-TTCATTCCTTTTTTTGGACACTGGTGG-3′ (SEQ ID NO: 1011)5′-UUUUUGGACACUGGUGGCUCAUUAC-3′ (SEQ ID NO: 1170)3′-AAAAAAACCUGUGACCACCGAGUAAUG-5′ (SEQ ID NO: 256) HIF-1α-2933 Target:5′-TTTTTTTGGACACTGGTGGCTCATTAC-3′ (SEQ ID NO: 1012)5′-GCAGUCUAUUUAUAUUUUCUACAUC-3′ (SEQ ID NO: 1171)3′-UUCGUCAGAUAAAUAUAAAAGAUGUAG-5′ (SEQ ID NO: 258) HIF-1α-2963 Target:5′-AAGCAGTCTATTTATATTTTCTACATC-3′ (SEQ ID NO: 1014)5′-AGUCUAUUUAUAUUUUCUACAUCUA-3′ (SEQ ID NO: 1172)3′-CGUCAGAUAAAUAUAAAAGAUGUAGAU-5′ (SEQ ID NO: 259) HIF-1α-2965 Target:5′-GCAGTCTATTTATATTTTCTACATCTA-3′ (SEQ ID NO: 1015)5′-AUUUAUAUUUUCUACAUCUAAUUUU-3′ (SEQ ID NO: 1173)3′-GAUAAAUAUAAAAGAUGUAGAUUAAAA-5′ (SEQ ID NO: 260) HIF-1α-2970 Target:5′-CTATTTATATTTTCTACATCTAATTTT-3′ (SEQ ID NO: 1016)5′-UAAUUUACAUUAAUGCUCUUUUUUA-3′ (SEQ ID NO: 1174)3′-GAAUUAAAUGUAAUUACGAGAAAAAAU-5′ (SEQ ID NO: 271) HIF-1α-3055 Target:5′-CTTAATTTACATTAATGCTCTTTTTTA-3′ (SEQ ID NO: 1027)5′-UUUAAUGCUGGAUCACAGACAGCUC-3′ (SEQ ID NO: 1175)3′-AGAAAUUACGACCUAGUGUCUGUCGAG-5′ (SEQ ID NO: 277) HIF-1α-3088 Target:5′-TCTTTAATGCTGGATCACAGACAGCTC-3′ (SEQ ID NO: 1033)5′-CUCAUUUUCUCAGUUUUUUGGUAUU-3′ (SEQ ID NO: 1176)3′-UCGAGUAAAAGAGUCAAAAAACCAUAA-5′ (SEQ ID NO: 279) HIF-1α-3110 Target:5′-AGCTCATTTTCTCAGTTTTTTGGTATT-3′ (SEQ ID NO: 1035)5′-UUUUUUUUCACAUUUUACAUAAAUA-3′ (SEQ ID NO: 1177)3′-GGAAAAAAAAGUGUAAAAUGUAUUUAU-5′ (SEQ ID NO: 294) HIF-1α-3310 Target:5′-CCTTTTTTTTCACATTTTACATAAATA-3′ (SEQ ID NO: 1050)5′-CACAAUUGCACAAUAUAUUUUCUUA-3′ (SEQ ID NO: 1178)3′-CGGUGUUAACGUGUUAUAUAAAAGAAU-5′ (SEQ ID NO: 298) HIF-1α-3364 Target:5′-GCCACAATTGCACAATATATTTTCTTA-3′ (SEQ ID NO: 1054)5′-CAAUUGCACAAUAUAUUUUCUUAAA-3′ (SEQ ID NO: 1179)3′-GUGUUAACGUGUUAUAUAAAAGAAUUU-5′ (SEQ ID NO: 299) HIF-1α-3366 Target:5′-CACAATTGCACAATATATTTTCTTAAA-3′ (SEQ ID NO: 1055)5′-CAAUAUAUUUUCUUAAAAAAUACCA-3′ (SEQ ID NO: 1180)3′-GUGUUAUAUAAAAGAAUUUUUUAUGGU-5′ (SEQ ID NO: 301) HIF-1α-3374 Target:5′-CACAATATATTTTCTTAAAAAATACCA-3′ (SEQ ID NO: 1057)5′-UAAAACUAGUUUUUAAGAAGAAAUU-3′ (SEQ ID NO: 1181)3′-AUAUUUUGAUCAAAAAUUCUUCUUUAA-5′ (SEQ ID NO: 305) HIF-1α-3430 Target:5′-TATAAAACTAGTTTTTAAGAAGAAATT-3′ (SEQ ID NO: 1061)5′-AGAAAUUUUUUUUGGCCUAUGAAAU-3′ (SEQ ID NO: 1182)3′-CUUCUUUAAAAAAAACCGGAUACUUUA-5′ (SEQ ID NO: 307) HIF-1α-3448 Target:5′-GAAGAAATTTTTTTTGGCCTATGAAAT-3′ (SEQ ID NO: 1063)5′-AAAUUUUUUUUGGCCUAUGAAAUUG-3′ (SEQ ID NO: 1183)3′-UCUUUAAAAAAAACCGGAUACUUUAAC-5′ (SEQ ID NO: 308) HIF-1α-3450 Target:5′-AGAAATTTTTTTTGGCCTATGAAATTG-3′ (SEQ ID NO: 1064)5′-UGUGGCAUUUAUUUGGAUAAAAUUC-3′ (SEQ ID NO: 1184)3′-AUACACCGUAAAUAAACCUAUUUUAAG-5′ (SEQ ID NO: 317) HIF-1α-3598 Target:5′-TATGTGGCATTTATTTGGATAAAATTC-3′ (SEQ ID NO: 1073)5′-AAAAUUCUCAAUUCAGAGAAAUCAU-3′ (SEQ ID NO: 1185)3′-UAUUUUAAGAGUUAAGUCUCUUUAGUA-5′ (SEQ ID NO: 327) HIF-1α-3616 Target:5′-ATAAAATTCTCAATTCAGAGAAATCAT-3′ (SEQ ID NO: 1083)5′-GUUUCUAUAGUCACUUUGCCAGCUC-3′ (SEQ ID NO: 1186)3′-UACAAAGAUAUCAGUGAAACGGUCGAG-5′ (SEQ ID NO: 329) HIF-1α-3646 Target:5′-ATGTTTCTATAGTCACTTTGCCAGCTC-3′ (SEQ ID NO: 1085)5′-CAAAAGAAAACAAUACCCUAUGUAG-3′ (SEQ ID NO: 1187)3′-GAGUUUUCUUUUGUUAUGGGAUACAUC-5′ (SEQ ID NO: 331) HIF-1α-3670 Target:5′-CTCAAAAGAAAACAATACCCTATGTAG-3′ (SEQ ID NO: 1087)5′-UUCUGCCUACCCUGUUGGUAUAAAG-3′ (SEQ ID NO: 1188)3′-ACAAGACGGAUGGGACAACCAUAUUUC-5′ (SEQ ID NO: 332) HIF-1α-3743 Target:5′-TGTTCTGCCTACCCTGTTGGTATAAAG-3′ (SEQ ID NO: 1088)5′-AGAAAAAAAAAAUCAUGCAUUCUUA-3′ (SEQ ID NO: 1189)3′-GUUCUUUUUUUUUUAGUACGUAAGAAU-5′ (SEQ ID NO: 339) HIF-1α-3791 Target:5′-CAAGAAAAAAAAAATCATGCATTCTTA-3′ (SEQ ID NO: 1095)5′-UUUUAUGCACUUUGUCGCUAUUAAC-3′ (SEQ ID NO: 1190)3′-CUAAAAUACGUGAAACAGCGAUAAUUG-5′ (SEQ ID NO: 341) HIF-1α-3861 Target:5′-GATTTTATGCACTTTGTCGCTATTAAC-3′ (SEQ ID NO: 1097)5′-UUAUGCACUUUGUCGCUAUUAACAU-3′ (SEQ ID NO: 1191)3′-AAAAUACGUGAAACAGCGAUAAUUGUA-5′ (SEQ ID NO: 342) HIF-1α-3863 Target:5′-TTTTATGCACTTTGTCGCTATTAACAT-3′ (SEQ ID NO: 1098)5′-AUUAACAUCCUUUUUUUCAUGUAGA-3′ (SEQ ID NO: 1192)3′-GAUAAUUGUAGGAAAAAAAGUACAUCU-5′ (SEQ ID NO: 350) HIF-1α-3880 Target:5′-CTATTAACATCCTTTTTTTCATGTAGA-3′ (SEQ ID NO: 1106)5′-AAUUUUAGAAGCAUUAUUUUAGGAA-3′ (SEQ ID NO: 1193)3′-CAUUAAAAUCUUCGUAAUAAAAUCCUU-5′ (SEQ ID NO: 353) HIF-1α-3920 Target:5′-GTAATTTTAGAAGCATTATTTTAGGAA-3′ (SEQ ID NO: 1109)5′-UUUUAGAAGCAUUAUUUUAGGAAUA-3′ (SEQ ID NO: 1194)3′-UUAAAAUCUUCGUAAUAAAAUCCUUAU-5′ (SEQ ID NO: 354) HIF-1α-3922 Target:5′-AATTTTAGAAGCATTATTTTAGGAATA-3′ (SEQ ID NO: 1110)5′-UUAGAAGCAUUAUUUUAGGAAUAUA-3′ (SEQ ID NO: 1195)3′-AAAAUCUUCGUAAUAAAAUCCUUAUAU-5′ (SEQ ID NO: 355) HIF-1α-3924 Target:5′-TTTTAGAAGCATTATTTTAGGAATATA-3′ (SEQ ID NO: 1111)5′-UAAAUAUCUUGUUUUUUCUAUGUAC-3′ (SEQ ID NO: 1196)3′-UCAUUUAUAGAACAAAAAAGAUACAUG-5′ (SEQ ID NO: 359) HIF-1α-3961 Target:5′-AGTAAATATCTTGTTTTTTCTATGTAC-3′ (SEQ ID NO: 1115)5′-UUCCUUUUGCUCUUUGUGGUUGGAU-3′ (SEQ ID NO: 1197)3′-GUAAGGAAAACGAGAAACACCAACCUA-5′ (SEQ ID NO: 364) HIF-1α-4003 Target:5′-CATTCCTTTTGCTCTTTGTGGTTGGAT-3′ (SEQ ID NO: 1120)5′-UCCUUUUGCUCUUUGUGGUUGGAUC-3′ (SEQ ID NO: 1198)3′-UAAGGAAAACGAGAAACACCAACCUAG-5′ (SEQ ID NO: 365) HIF-1α-4004 Target:5′-ATTCCTTTTGCTCTTTGTGGTTGGATC-3′ (SEQ ID NO: 1121)5′-CCUUUUGCUCUUUGUGGUUGGAUCU-3′ (SEQ ID NO: 1199)3′-AAGGAAAACGAGAAACACCAACCUAGA-5′ (SEQ ID NO: 366) HIF-1α-4005 Target:5′-TTCCTTTTGCTCTTTGTGGTTGGATCT-3′ (SEQ ID NO: 1122)5′-CUUUUGCUCUUUGUGGUUGGAUCUA-3′ (SEQ ID NO: 1200)3′-AGGAAAACGAGAAACACCAACCUAGAU-5′ (SEQ ID NO: 367) HIF-1α-4006 Target:5′-TCCTTTTGCTCTTTGTGGTTGGATCTA-3′ (SEQ ID NO: 1123)5′-UUUUGCUCUUUGUGGUUGGAUCUAA-3′ (SEQ ID NO: 1201)3′-GGAAAACGAGAAACACCAACCUAGAUU-5′ (SEQ ID NO: 368) HIF-1α-4007 Target:5′-CCTTTTGCTCTTTGTGGTTGGATCTAA-3′ (SEQ ID NO: 1124)5′-UUUGCUCUUUGUGGUUGGAUCUAAC-3′ (SEQ ID NO: 1202)3′-GAAAACGAGAAACACCAACCUAGAUUG-5′ (SEQ ID NO: 369) HIF-1α-4008 Target:5′-CTTTTGCTCTTTGTGGTTGGATCTAAC-3′ (SEQ ID NO: 1125)5′-UUGCUCUUUGUGGUUGGAUCUAACA-3′ (SEQ ID NO: 1203)3′-AAAACGAGAAACACCAACCUAGAUUGU-5′ (SEQ ID NO: 370) HIF-1α-4009 Target:5′-TTTTGCTCTTTGTGGTTGGATCTAACA-3′ (SEQ ID NO: 1126)5′-UGCUCUUUGUGGUUGGAUCUAACAC-3′ (SEQ ID NO: 1204)3′-AAACGAGAAACACCAACCUAGAUUGUG-5′ (SEQ ID NO: 371) HIF-1α-4010 Target:5′-TTTGCTCTTTGTGGTTGGATCTAACAC-3′ (SEQ ID NO: 1127)5′-AGAAACCUACUGCAGGGUGAAGAAU-3′ (SEQ ID NO: 1205)3′-CGUCUUUGGAUGACGUCCCACUUCUUA-5′ (SEQ ID NO: 232) HIF-1α-2856 Target:5′-GCAGAAACCTACTGCAGGGTGAAGAAT-3′ (SEQ ID NO: 988)5′-AAUAUUGAAAUUCCUUUAGAUAGCA-3′ (SEQ ID NO: 1206)3′-GUUUAUAACUUUAAGGAAAUCUAUCGU-5′ (SEQ ID NO: 102) HIF-1α-1122 Target:5′-CAAATATTGAAATTCCTTTAGATAGCA-3′ (SEQ ID NO: 858)5′-AAACCUACUGCAGGGUGAAGAAUUA-3′ (SEQ ID NO: 1207)3′-UCUUUGGAUGACGUCCCACUUCUUAAU-5′ (SEQ ID NO: 233) HIF-1α-2858 Target:5′-AGAAACCTACTGCAGGGTGAAGAATTA-3′ (SEQ ID NO: 989)5′-CUACUGCAGGGUGAAGAAUUACUCA-3′ (SEQ ID NO: 1208)3′-UGGAUGACGUCCCACUUCUUAAUGAGU-5′ (SEQ ID NO: 235) HIF-1α-2862 Target:5′-ACCTACTGCAGGGTGAAGAATTACTCA-3′ (SEQ ID NO: 991)5′-UUUUUUUUCACAUUUUACAUAAAUA-3′ (SEQ ID NO: 1209)3′-GGAAAAAAAAGUGUAAAAUGUAUUUAU-5′ (SEQ ID NO: 294) HIF-1α-3310 Target:5′-CCTTTTTTTTCACATTTTACATAAATA-3′ (SEQ ID NO: 1050)5′-UCAAGCAACUGUCAUAUAUAACACC-3′ (SEQ ID NO: 1210)3′-UGAGUUCGUUGACAGUAUAUAUUGUGG-5′ (SEQ ID NO: 166) HIF-1α-1385 Target:5′-ACTCAAGCAACTGTCATATATAACACC-3′ (SEQ ID NO: 922)5′-CUUUGGAUCAAGUUAACUGAGCUUU-3′ (SEQ ID NO: 1211)3′-UCGAAACCUAGUUCAAUUGACUCGAAA-5′ (SEQ ID NO: 249) HIF-1α-2890 Target:5′-AGCTTTGGATCAAGTTAACTGAGCTTT-3′ (SEQ ID NO: 1005)5′-CGAAGCUUUUUUCUCAGAAUGAAGU-3′ (SEQ ID NO: 1212)3′-UCGCUUCGAAAAAAGAGUCUUACUUCA-5′ (SEQ ID NO: 79) HIF-1α-921 Target:5′-AGCGAAGCTTTTTTCTCAGAATGAAGT-3′ (SEQ ID NO: 835)5′-CUCUUUGUGGUUGGAUCUAACACUA-3′ (SEQ ID NO: 1213)3′-ACGAGAAACACCAACCUAGAUUGUGAU-5′ (SEQ ID NO: 372) HIF-1α-4012 Target:5′-TGCTCTTTGTGGTTGGATCTAACACTA-3′ (SEQ ID NO: 1128)5′-GCAUUAUUUUAGGAAUAUAUAGUUG-3′ (SEQ ID NO: 1214)3′-UUCGUAAUAAAAUCCUUAUAUAUCAAC-5′ (SEQ ID NO: 358) HIF-1α-3930 Target:5′-AAGCATTATTTTAGGAATATATAGTTG-3′ (SEQ ID NO: 1114)5′-UUACCACAGCUGACCAGUUAUGAUU-3′ (SEQ ID NO: 1215)3′-CUAAUGGUGUCGACUGGUCAAUACUAA-5′ (SEQ ID NO: 224) HIF-1α-2802 Target:5′-GATTACCACAGCTGACCAGTTATGATT-3′ (SEQ ID NO: 980)5′-AAACUCAAGCAACUGUCAUAUAUAA-3′ (SEQ ID NO: 1216)3′-ACUUUGAGUUCGUUGACAGUAUAUAUU-5′ (SEQ ID NO: 164) HIF-1α-1381 Target:5′-TGAAACTCAAGCAACTGTCATATATAA-3′ (SEQ ID NO: 920)5′-UGGAUUACCACAGCUGACCAGUUAU-3′ (SEQ ID NO: 1217)3′-UCACCUAAUGGUGUCGACUGGUCAAUA-5′ (SEQ ID NO: 222) HIF-1α-2798 Target:5′-AGTGGATTACCACAGCTGACCAGTTAT-3′ (SEQ ID NO: 978)5′-GCAGUCUAUUUAUAUUUUCUACAUC-3′ (SEQ ID NO: 1218)3′-UUCGUCAGAUAAAUAUAAAAGAUGUAG-5′ (SEQ ID NO: 258) HIF-1α-2963 Target:5′-AAGCAGTCTATTTATATTTTCTACATC-3′ (SEQ ID NO: 1014)5′-GAUUUUCUCCCUUCAACAAACAGAA-3′ (SEQ ID NO: 1219)3′-AACUAAAAGAGGGAAGUUGUUUGUCUU-5′ (SEQ ID NO: 179) HIF-1α-1478 Target:5′-TTGATTTTCTCCCTTCAACAAACAGAA-3′ (SEQ ID NO: 935)5′-UUACUCAGAGCUUUGGAUCAAGUUA-3′ (SEQ ID NO: 1220)3′-UUAAUGAGUCUCGAAACCUAGUUCAAU-5′ (SEQ ID NO: 244) HIF-1α-2880 Target:5′-AATTACTCAGAGCTTTGGATCAAGTTA-3′ (SEQ ID NO: 1000)5′-GAGUAAUUUUAGAAGCAUUAUUUUA-3′ (SEQ ID NO: 1221)3′-AACUCAUUAAAAUCUUCGUAAUAAAAU-5′ (SEQ ID NO: 351) HIF-1α-3916 Target:5′-TTGAGTAATTTTAGAAGCATTATTTTA-3′ (SEQ ID NO: 1107)5′-UAAUUUUAGAAGCCUGGCUACAAUA-3′ (SEQ ID NO: 1222)3′-AGAUUAAAAUCUUCGGACCGAUGUUAU-5′ (SEQ ID NO: 262) HIF-1α-2988 Target:5′-TCTAATTTTAGAAGCCTGGCTACAATA-3′ (SEQ ID NO: 1018)5′-AUGCACUUUGUCGCUAUUAACAUCC-3′ (SEQ ID NO: 1223)3′-AAUACGUGAAACAGCGAUAAUUGUAGG-5′ (SEQ ID NO: 343) HIF-1α-3865 Target:5′-TTATGCACTTTGTCGCTATTAACATCC-3′ (SEQ ID NO: 1099)5′-CAGCAGAAACCUACUGCAGGGUGAA-3′ (SEQ ID NO: 1224)3′-CCGUCGUCUUUGGAUGACGUCCCACUU-5′ (SEQ ID NO: 230) HIF-1α-2852 Target:5′-GGCAGCAGAAACCTACTGCAGGGTGAA-3′ (SEQ ID NO: 986)5′-AGAAUUACUCAGAGCUUUGGAUCAA-3′ (SEQ ID NO: 1225)3′-CUUCUUAAUGAGUCUCGAAACCUAGUU-5′ (SEQ ID NO: 242) HIF-1α-2876 Target:5′-GAAGAATTACTCAGAGCTTTGGATCAA-3′ (SEQ ID NO: 998)5′-GAAGAAUUACUCAGAGCUUUGGAUC-3′ (SEQ ID NO: 1226)3′-CACUUCUUAAUGAGUCUCGAAACCUAG-5′ (SEQ ID NO: 241) HIF-1α-2874 Target:5′-GTGAAGAATTACTCAGAGCTTTGGATC-3′ (SEQ ID NO: 997)5′-ACUCAGAGCUUUGGAUCAAGUUAAC-3′ (SEQ ID NO: 1227)3′-AAUGAGUCUCGAAACCUAGUUCAAUUG-5′ (SEQ ID NO: 245) HIF-1α-2882 Target:5′-TTACTCAGAGCTTTGGATCAAGTTAAC-3′ (SEQ ID NO: 1001)

TABLE 4 Selected Mouse Anti-HIF-1α DsiRNAs (Asymmetrics)5′-CCGCGGGCGCGCGCGUUGGGUGCtg-3′ (SEQ ID NO: 1486)3′-CGGGCGCCCGCGCGCGCAACCCACGAC-5′ (SEQ ID NO: 1414) HIF-1α-m38 Targ:5′-GCCCGCGGGCGCGCGCGTTGGGTGCTG-3′ (SEQ ID NO: 1558)5′-GCGGGCGCGCGCGUUGGGUGCUGag-3′ (SEQ ID NO: 1487)3′-GGCGCCCGCGCGCGCAACCCACGACUC-5′ (SEQ ID NO: 1415) HIF-1α-m40 Targ:5′-CCGCGGGCGCGCGCGTTGGGTGCTGAG-3′ (SEQ ID NO: 1559)5′-CGGGCGCGCGCGUUGGGUGCUGAgc-3′ (SEQ ID NO: 1488)3′-GCGCCCGCGCGCGCAACCCACGACUCG-5′ (SEQ ID NO: 1416) HIF-1α-m41 Targ:5′-CGCGGGCGCGCGCGTTGGGTGCTGAGC-3′ (SEQ ID NO: 1560)5′-GGGCGCGCGCGUUGGGUGCUGAGcg-3′ (SEQ ID NO: 1489)3′-CGCCCGCGCGCGCAACCCACGACUCGC-5′ (SEQ ID NO: 1417) HIF-1α-m42 Targ:5′-GCGGGCGCGCGCGTTGGGTGCTGAGCG-3′ (SEQ ID NO: 1561)5′-GGCGCGCGCGUUGGGUGCUGAGCgg-3′ (SEQ ID NO: 1490)3′-GCCCGCGCGCGCAACCCACGACUCGCC-5′ (SEQ ID NO: 1418) HIF-1α-m43 Targ:5′-CGGGCGCGCGCGTTGGGTGCTGAGCGG-3′ (SEQ ID NO: 1562)5′-GCGCGCGCGUUGGGUGCUGAGCGgg-3′ (SEQ ID NO: 1491)3′-CCCGCGCGCGCAACCCACGACUCGCCC-5′ (SEQ ID NO: 1419) HIF-1α-m44 Targ:5′-GGGCGCGCGCGTTGGGTGCTGAGCGGG-3′ (SEQ ID NO: 1563)5′-CGCGCGCGUUGGGUGCUGAGCGGgc-3′ (SEQ ID NO: 1492)3′-CCGCGCGCGCAACCCACGACUCGCCCG-5′ (SEQ ID NO: 1420) HIF-1α-m45 Targ:5′-GGCGCGCGCGTTGGGTGCTGAGCGGGC-3′ (SEQ ID NO: 1564)5′-GCGCGCGUUGGGUGCUGAGCGGGcg-3′ (SEQ ID NO: 1493)3′-CGCGCGCGCAACCCACGACUCGCCCGC-5′ (SEQ ID NO: 1421) HIF-1α-m46 Targ:5′-GCGCGCGCGTTGGGTGCTGAGCGGGCG-3′ (SEQ ID NO: 1565)5′-CGCGCGUUGGGUGCUGAGCGGGCgc-3′ (SEQ ID NO: 1494)3′-GCGCGCGCAACCCACGACUCGCCCGCG-5′ (SEQ ID NO: 1422) HIF-1α-m47 Targ:5′-CGCGCGCGTTGGGTGCTGAGCGGGCGC-3′ (SEQ ID NO: 1566)5′-CGCGUUGGGUGCUGAGCGGGCGCgc-3′ (SEQ ID NO: 1495)3′-GCGCGCAACCCACGACUCGCCCGCGCG-5′ (SEQ ID NO: 1423) HIF-1α-m49 Targ:5′-CGCGCGTTGGGTGCTGAGCGGGCGCGC-3′ (SEQ ID NO: 1567)5′-GCGUUGGGUGCUGAGCGGGCGCGcg-3′ (SEQ ID NO: 1496)3′-CGCGCAACCCACGACUCGCCCGCGCGC-5′ (SEQ ID NO: 1424) HIF-1α-m50 Targ:5′-GCGCGTTGGGTGCTGAGCGGGCGCGCG-3′ (SEQ ID NO: 1568)5′-CGUUGGGUGCUGAGCGGGCGCGCgc-3′ (SEQ ID NO: 1497)3′-GCGCAACCCACGACUCGCCCGCGCGCG-5′ (SEQ ID NO: 1425) HIF-1α-m51 Targ:5′-CGCGTTGGGTGCTGAGCGGGCGCGCGC-3′ (SEQ ID NO: 1569)5′-GUUGGGUGCUGAGCGGGCGCGCGca-3′ (SEQ ID NO: 1498)3′-CGCAACCCACGACUCGCCCGCGCGCGU-5′ (SEQ ID NO: 1426) HIF-1α-m52 Targ:5′-GCGTTGGGTGCTGAGCGGGCGCGCGCA-3′ (SEQ ID NO: 1570)5′-UUGGGUGCUGAGCGGGCGCGCGCac-3′ (SEQ ID NO: 1499)3′-GCAACCCACGACUCGCCCGCGCGCGUG-5′ (SEQ ID NO: 1427) HIF-1α-m53 Targ:5′-CGTTGGGTGCTGAGCGGGCGCGCGCAC-3′ (SEQ ID NO: 1571)5′-GGGUGCUGAGCGGGCGCGCGCACcc-3′ (SEQ ID NO: 1500)3′-AACCCACGACUCGCCCGCGCGCGUGGG-5′ (SEQ ID NO: 1428) HIF-1α-m55 Targ:5′-TTGGGTGCTGAGCGGGCGCGCGCACCC-3′ (SEQ ID NO: 1572)5′-CUCGCCGCGCGCCCGAGCGCGCCtc-3′ (SEQ ID NO: 1501)3′-GGGAGCGGCGCGCGGGCUCGCGCGGAG-5′ (SEQ ID NO: 1429) HIF-1α-m97 Targ:5′-CCCTCGCCGCGCGCCCGAGCGCGCCTC-3′ (SEQ ID NO: 1573)5′-UCGCCGCGCGCCCGAGCGCGCCUcc-3′ (SEQ ID NO: 1502)3′-GGAGCGGCGCGCGGGCUCGCGCGGAGG-5′ (SEQ ID NO: 1430) HIF-1α-m98 Targ:5′-CCTCGCCGCGCGCCCGAGCGCGCCTCC-3′ (SEQ ID NO: 1574)5′-CGCCGCGCGCCCGAGCGCGCCUCcg-3′ (SEQ ID NO: 1503)3′-GAGCGGCGCGCGGGCUCGCGCGGAGGC-5′ (SEQ ID NO: 1431) HIF-1α-m99 Targ:5′-CTCGCCGCGCGCCCGAGCGCGCCTCCG-3′ (SEQ ID NO: 1575)5′-GCCGCGCGCCCGAGCGCGCCUCCgc-3′ (SEQ ID NO: 1504)3′-AGCGGCGCGCGGGCUCGCGCGGAGGCG-5′ (SEQ ID NO: 1432) HIF-1α-m100 Targ:5′-TCGCCGCGCGCCCGAGCGCGCCTCCGC-3′ (SEQ ID NO: 1576)5′-UGCCGCUGCUUCAGCGCCUCAGUgc-3′ (SEQ ID NO: 1505)3′-GGACGGCGACGAAGUCGCGGAGUCACG-5′ (SEQ ID NO: 1433) HIF-1α-m139 Targ:5′-CCTGCCGCTGCTTCAGCGCCTCAGTGC-3′ (SEQ ID NO: 1577)5′-CCGCUGCUUCAGCGCCUCAGUGCac-3′ (SEQ ID NO: 1506)3′-ACGGCGACGAAGUCGCGGAGUCACGUG-5′ (SEQ ID NO: 1434) HIF-1α-m141 Targ:5′-TGCCGCTGCTTCAGCGCCTCAGTGCAC-3′ (SEQ ID NO: 1578)5′-UGCUUCAGCGCCUCAGUGCACAGag-3′ (SEQ ID NO: 1507)3′-CGACGAAGUCGCGGAGUCACGUGUCUC-5′ (SEQ ID NO: 1435) HIF-1α-m145 Targ:5′-GCTGCTTCAGCGCCTCAGTGCACAGAG-3′ (SEQ ID NO: 1579)5′-GCUUCAGCGCCUCAGUGCACAGAgc-3′ (SEQ ID NO: 1508)3′-GACGAAGUCGCGGAGUCACGUGUCUCG-5′ (SEQ ID NO: 1436) HIF-1α-m146 Targ:5′-CTGCTTCAGCGCCTCAGTGCACAGAGC-3′ (SEQ ID NO: 1580)5′-UUCAGCGCCUCAGUGCACAGAGCct-3′ (SEQ ID NO: 1509)3′-CGAAGUCGCGGAGUCACGUGUCUCGGA-5′ (SEQ ID NO: 1437) HIF-1α-m148 Targ:5′-GCTTCAGCGCCTCAGTGCACAGAGCCT-3′ (SEQ ID NO: 1581)5′-GCGCCUCAGUGCACAGAGCCUCCtc-3′ (SEQ ID NO: 1510)3′-GUCGCGGAGUCACGUGUCUCGGAGGAG-5′ (SEQ ID NO: 1438) HIF-1α-m152 Targ:5′-CAGCGCCTCAGTGCACAGAGCCTCCTC-3′ (SEQ ID NO: 1582)5′-GCCGGAGCUCAGCGAGCGCAGCCtg-3′ (SEQ ID NO: 1511)3′-CUCGGCCUCGAGUCGCUCGCGUCGGAC-5′ (SEQ ID NO: 1439) HIF-1α-m271 Targ:5′-GAGCCGGAGCTCAGCGAGCGCAGCCTG-3′ (SEQ ID NO: 1583)5′-GCUCAGCGAGCGCAGCCUGCAGCtc-3′ (SEQ ID NO: 1512)3′-CUCGAGUCGCUCGCGUCGGACGUCGAG-5′ (SEQ ID NO: 1440) HIF-1α-m277 Targ:5′-GAGCTCAGCGAGCGCAGCCTGCAGCTC-3′ (SEQ ID NO: 1584)5′-GCGAGCGCAGCCUGCAGCUCCCGcc-3′ (SEQ ID NO: 1513)3′-GUCGCUCGCGUCGGACGUCGAGGGCGG-5′ (SEQ ID NO: 1441) HIF-1α-m282 Targ:5′-CAGCGAGCGCAGCCTGCAGCTCCCGCC-3′ (SEQ ID NO: 1585)5′-CGAGCGCAGCCUGCAGCUCCCGCct-3′ (SEQ ID NO: 1514)3′-UCGCUCGCGUCGGACGUCGAGGGCGGA-5′ (SEQ ID NO: 1442) HIF-1α-m283 Targ:5′-AGCGAGCGCAGCCTGCAGCTCCCGCCT-3′ (SEQ ID NO: 1586)5′-GAGCGCAGCCUGCAGCUCCCGCCtc-3′ (SEQ ID NO: 1515)3′-CGCUCGCGUCGGACGUCGAGGGCGGAG-5′ (SEQ ID NO: 1443) HIF-1α-m284 Targ:5′-GCGAGCGCAGCCTGCAGCTCCCGCCTC-3′ (SEQ ID NO: 1587)5′-GCGCAGCCUGCAGCUCCCGCCUCgc-3′ (SEQ ID NO: 1516)3′-CUCGCGUCGGACGUCGAGGGCGGAGCG-5′ (SEQ ID NO: 1444) HIF-1α-m286 Targ:5′-GAGCGCAGCCTGCAGCTCCCGCCTCGC-3′ (SEQ ID NO: 1588)5′-CAGCCUGCAGCUCCCGCCUCGCCgt-3′ (SEQ ID NO: 1517)3′-GCGUCGGACGUCGAGGGCGGAGCGGCA-5′ (SEQ ID NO: 1445) HIF-1α-m289 Targ:5′-CGCAGCCTGCAGCTCCCGCCTCGCCGT-3′ (SEQ ID NO: 1589)5′-GACUUGUCUCUUUCUCCGCGCGCgc-3′ (SEQ ID NO: 1518)3′-ACCUGAACAGAGAAAGAGGCGCGCGCG-5′ (SEQ ID NO: 1446) HIF-1α-m348 Targ:5′-TGGACTTGTCTCTTTCTCCGCGCGCGC-3′ (SEQ ID NO: 1590)5′-CUUGUCUCUUUCUCCGCGCGCGCgg-3′ (SEQ ID NO: 1519)3′-CUGAACAGAGAAAGAGGCGCGCGCGCC-5′ (SEQ ID NO: 1447) HIF-1α-m350 Targ:5′-GACTTGTCTCTTTCTCCGCGCGCGCGG-3′ (SEQ ID NO: 1591)5′-UGUCUCUUUCUCCGCGCGCGCGGac-3′ (SEQ ID NO: 1520)3′-GAACAGAGAAAGAGGCGCGCGCGCCUG-5′ (SEQ ID NO: 1448) HIF-1α-m352 Targ:5′-CTTGTCTCTTTCTCCGCGCGCGCGGAC-3′ (SEQ ID NO: 1592)5′-GUCUCUUUCUCCGCGCGCGCGGAca-3′ (SEQ ID NO: 1521)3′-AACAGAGAAAGAGGCGCGCGCGCCUGU-5′ (SEQ ID NO: 1449) HIF-1α-m353 Targ:5′-TTGTCTCTTTCTCCGCGCGCGCGGACA-3′ (SEQ ID NO: 1593)5′-UCUCUUUCUCCGCGCGCGCGGACag-3′ (SEQ ID NO: 1522)3′-ACAGAGAAAGAGGCGCGCGCGCCUGUC-5′ (SEQ ID NO: 1450) HIF-1α-m354 Targ:5′-TGTCTCTTTCTCCGCGCGCGCGGACAG-3′ (SEQ ID NO: 1594)5′-CUUUCUCCGCGCGCGCGGACAGAgc-3′ (SEQ ID NO: 1523)3′-GAGAAAGAGGCGCGCGCGCCUGUCUCG-5′ (SEQ ID NO: 1451) HIF-1α-m357 Targ:5′-CTCTTTCTCCGCGCGCGCGGACAGAGC-3′ (SEQ ID NO: 1595)5′-UUCUCCGCGCGCGCGGACAGAGCcg-3′ (SEQ ID NO: 1524)3′-GAAAGAGGCGCGCGCGCCUGUCUCGGC-5′ (SEQ ID NO: 1452) HIF-1α-m359 Targ:5′-CTTTCTCCGCGCGCGCGGACAGAGCCG-3′ (SEQ ID NO: 1596)5′-GCGCGCGCGGACAGAGCCGGCGUtt-3′ (SEQ ID NO: 1525)3′-GGCGCGCGCGCCUGUCUCGGCCGCAAA-5′ (SEQ ID NO: 1453) HIF-1α-m365 Targ:5′-CCGCGCGCGCGGACAGAGCCGGCGTTT-3′ (SEQ ID NO: 1597)5′-GAGCUCACAUCUUGAUAAAGCUUct-3′ (SEQ ID NO: 1526)3′-CACUCGAGUGUAGAACUAUUUCGAAGA-5′ (SEQ ID NO: 1454) HIF-1α-m597 Targ:5′-GTGAGCTCACATCTTGATAAAGCTTCT-3′ (SEQ ID NO: 1598)5′-CUCACAUCUUGAUAAAGCUUCUGtt-3′ (SEQ ID NO: 1527)3′-UCGAGUGUAGAACUAUUUCGAAGACAA-5′ (SEQ ID NO: 1455) HIF-1α-m600 Targ:5′-AGCTCACATCTTGATAAAGCTTCTGTT-3′ (SEQ ID NO: 1599)5′-GACUGUUUUUAUCUGAAAGCCCUag-3′ (SEQ ID NO: 1528)3′-ACCUGACAAAAAUAGACUUUCGGGAUC-5′ (SEQ ID NO: 1456) HIF-1α-m712 Targ:5′-TGGACTGTTTTTATCTGAAAGCCCTAG-3′ (SEQ ID NO: 1600)5′-CCCAUGACGUGCUUGGUGCUGAUtt-3′ (SEQ ID NO: 1529)3′-GUGGGUACUGCACGAACCACGACUAAA-5′ (SEQ ID NO: 1457) HIF-1α-m1093 Targ:5′-CACCCATGACGTGCTTGGTGCTGATTT-3′ (SEQ ID NO: 1601)5′-UACAAGCUGCCUUUUUGAUAAGCtt-3′ (SEQ ID NO: 1530)3′-CUAUGUUCGACGGAAAAACUAUUCGAA-5′ (SEQ ID NO: 1458) HIF-1α-m1593 Targ:5′-GATACAAGCTGCCTTTTTGATAAGCTT-3′ (SEQ ID NO: 1602)5′-CAAGCUGCCUUUUUGAUAAGCUUaa-3′ (SEQ ID NO: 1531)3′-AUGUUCGACGGAAAAACUAUUCGAAUU-5′ (SEQ ID NO: 1459) HIF-1α-m1595 Targ:5′-TACAAGCTGCCTTTTTGATAAGCTTAA-3′ (SEQ ID NO: 1603)5′-AAGCUGCCUUUUUGAUAAGCUUAag-3′ (SEQ ID NO: 1532)3′-UGUUCGACGGAAAAACUAUUCGAAUUC-5′ (SEQ ID NO: 1460) HIF-1α-m1596 Targ:5′-ACAAGCTGCCTTTTTGATAAGCTTAAG-3′ (SEQ ID NO: 1604)5′-CUGCCUUUUUGAUAAGCUUAAGAag-3′ (SEQ ID NO: 1533)3′-UCGACGGAAAAACUAUUCGAAUUCUUC-5′ (SEQ ID NO: 1461) HIF-1α-m1599 Targ:5′-AGCTGCCTTTTTGATAAGCTTAAGAAG-3′ (SEQ ID NO: 1605)5′-UGCUCUCACUCUGCUGGCUCCAGct-3′ (SEQ ID NO: 1534)3′-CUACGAGAGUGAGACGACCGAGGUCGA-5′ (SEQ ID NO: 1462) HIF-1α-m1632 Targ:5′-GATGCTCTCACTCTGCTGGCTCCAGCT-3′ (SEQ ID NO: 1606)5′-GCUCUCACUCUGCUGGCUCCAGCtg-3′ (SEQ ID NO: 1535)3′-UACGAGAGUGAGACGACCGAGGUCGAC-5′ (SEQ ID NO: 1463) HIF-1α-m1633 Targ:5′-ATGCTCTCACTCTGCTGGCTCCAGCTG-3′ (SEQ ID NO: 1607)5′-CUCUCACUCUGCUGGCUCCAGCUgc-3′ (SEQ ID NO: 1536)3′-ACGAGAGUGAGACGACCGAGGUCGACG-5′ (SEQ ID NO: 1464) HIF-1α-m1634 Targ:5′-TGCTCTCACTCTGCTGGCTCCAGCTGC-3′ (SEQ ID NO: 1608)5′-CUGCUGGCUCCAGCUGCCGGCGAca-3′ (SEQ ID NO: 1537)3′-GAGACGACCGAGGUCGACGGCCGCUGU-5′ (SEQ ID NO: 1465) HIF-1α-m1642 Targ:5′-CTCTGCTGGCTCCAGCTGCCGGCGACA-3′ (SEQ ID NO: 1609)5′-UCGAAGUAGUGCUGAUCCUGCACtg-3′ (SEQ ID NO: 1538)3′-GAAGCUUCAUCACGACUAGGACGUGAC-5′ (SEQ ID NO: 1466) HIF-1α-m1830 Targ:5′-CTTCGAAGTAGTGCTGATCCTGCACTG-3′ (SEQ ID NO: 1610)5′-UAUUGCUUUGAUGUGGAUAGCGAta-3′ (SEQ ID NO: 1539)3′-UUAUAACGAAACUACACCUAUCGCUAU-5′ (SEQ ID NO: 1467) HIF-1α-m2041 Targ:5′-AATATTGCTTTGATGTGGATAGCGATA-3′ (SEQ ID NO: 1611)5′-UUGCUUUGAUGUGGAUAGCGAUAtg-3′ (SEQ ID NO: 1540)3′-AUAACGAAACUACACCUAUCGCUAUAC-5′ (SEQ ID NO: 1468) HIF-1α-m2043 Targ:5′-TATTGCTTTGATGTGGATAGCGATATG-3′ (SEQ ID NO: 1612)5′-GCUUUGAUGUGGAUAGCGAUAUGgt-3′ (SEQ ID NO: 1541)3′-AACGAAACUACACCUAUCGCUAUACCA-5′ (SEQ ID NO: 1469) HIF-1α-m2045 Targ:5′-TTGCTTTGATGTGGATAGCGATATGGT-3′ (SEQ ID NO: 1613)5′-GAUGGCUCCCUUUUUCAAGCAGCag-3′ (SEQ ID NO: 1542)3′-UACUACCGAGGGAAAAAGUUCGUCGUC-5′ (SEQ ID NO: 1470) HIF-1α-m2650 Targ:5′-ATGATGGCTCCCTTTTTCAAGCAGCAG-3′ (SEQ ID NO: 1614)5′-UUCUGUUGGUUAUUUUUGGACACtg-3′ (SEQ ID NO: 1543)3′-CAAAGACAACCAAUAAAAACCUGUGAC-5′ (SEQ ID NO: 1471) HIF-1α-m3030 Targ:5′-GTTTCTGTTGGTTATTTTTGGACACTG-3′ (SEQ ID NO: 1615)5′-UUAAGCCUGGAUCAUGAAGCUGUtg-3′ (SEQ ID NO: 1544)3′-ACAAUUCGGACCUAGUACUUCGACAAC-5′ (SEQ ID NO: 1472) HIF-1α-m3557 Targ:5′-TGTTAAGCCTGGATCATGAAGCTGTTG-3′ (SEQ ID NO: 1616)5′-CCUGGAUCAUGAAGCUGUUGAUCtt-3′ (SEQ ID NO: 1545)3′-UCGGACCUAGUACUUCGACAACUAGAA-5′ (SEQ ID NO: 1473) HIF-1α-m3562 Targ:5′-AGCCTGGATCATGAAGCTGTTGATCTT-3′ (SEQ ID NO: 1617)5′-CUGUUGAUCUUAUAAUGAUUCUUaa-3′ (SEQ ID NO: 1546)3′-UCGACAACUAGAAUAUUACUAAGAAUU-5′ (SEQ ID NO: 1474) HIF-1α-m3576 Targ:5′-AGCTGTTGATCTTATAATGATTCTTAA-3′ (SEQ ID NO: 1618)5′-GAUUCUUAAACUGUAUGGUUUCUtt-3′ (SEQ ID NO: 1547)3′-UACUAAGAAUUUGACAUACCAAAGAAA-5′ (SEQ ID NO: 1475) HIF-1α-m3592 Targ:5′-ATGATTCTTAAACTGTATGGTTTCTTT-3′ (SEQ ID NO: 1619)5′-GUAUGGUUUCUUUAUAUGGGUAAag-3′ (SEQ ID NO: 1548)3′-GACAUACCAAAGAAAUAUACCCAUUUC-5′ (SEQ ID NO: 1476) HIF-1α-m3604 Targ:5′-CTGTATGGTTTCTTTATATGGGTAAAG-3′ (SEQ ID NO: 1620)5′-UAGUAAACAUCUUGUUUUUUCUAtg-3′ (SEQ ID NO: 1549)3′-GUAUCAUUUGUAGAACAAAAAAGAUAC-5′ (SEQ ID NO: 1477) HIF-1α-m4023 Targ:5′-CATAGTAAACATCTTGTTTTTTCTATG-3′ (SEQ ID NO: 1621)5′-UUCGUUCCCUUGCUCUUUGUGGUtg-3′ (SEQ ID NO: 1550)3′-AAAAGCAAGGGAACGAGAAACACCAAC-5′ (SEQ ID NO: 1478) HIF-1α-m4064 Targ:5′-TTTTCGTTCCCTTGCTCTTTGTGGTTG-3′ (SEQ ID NO: 1622)5′-UCGUUCCCUUGCUCUUUGUGGUUgg-3′ (SEQ ID NO: 1551)3′-AAAGCAAGGGAACGAGAAACACCAACC-5′ (SEQ ID NO: 1479) HIF-1α-m4065 Targ:5′-TTTCGTTCCCTTGCTCTTTGTGGTTGG-3′ (SEQ ID NO: 1623)5′-CCCUUGCUCUUUGUGGUUGGGUCta-3′ (SEQ ID NO: 1552)3′-AAGGGAACGAGAAACACCAACCCAGAU-5′ (SEQ ID NO: 1480) HIF-1α-m4070 Targ:5′-TTCCCTTGCTCTTTGTGGTTGGGTCTA-3′ (SEQ ID NO: 1624)5′-UCCGCGCUCUCAGGGAGCUAUGUgg-3′ (SEQ ID NO: 1553)3′-AAAGGCGCGAGAGUCCCUCGAUACACC-5′ (SEQ ID NO: 1481) HIF-1α-m4549 Targ:5′-TTTCCGCGCTCTCAGGGAGCTATGTGG-3′ (SEQ ID NO: 1625)5′-CUGAUGUUUCUUUACUUUGCCAGct-3′ (SEQ ID NO: 1554)3′-UGGACUACAAAGAAAUGAAACGGUCGA-5′ (SEQ ID NO: 1482) HIF-1α-m4691 Targ:5′-ACCTGATGTTTCTTTACTTTGCCAGCT-3′ (SEQ ID NO: 1626)5′-UGAUGUUUCUUUACUUUGCCAGCtt-3′ (SEQ ID NO: 1555)3′-GGACUACAAAGAAAUGAAACGGUCGAA-5′ (SEQ ID NO: 1483) HIF-1α-m4692 Targ:5′-CCTGATGTTTCTTTACTTTGCCAGCTT-3′ (SEQ ID NO: 1627)5′-GAUGUUUCUUUACUUUGCCAGCUtt-3′ (SEQ ID NO: 1556)3′-GACUACAAAGAAAUGAAACGGUCGAAA-5′ (SEQ ID NO: 1484) HIF-1α-m4693 Targ:5′-CTGATGTTTCTTTACTTTGCCAGCTTT-3′ (SEQ ID NO: 1628)5′-GCCAGCUUUAAAAAAGUAUCUUAtg-3′ (SEQ ID NO: 1557)3′-AACGGUCGAAAUUUUUUCAUAGAAUAC-5′ (SEQ ID NO: 1485) HIF-1α-m4709 Targ:5′-TTGCCAGCTTTAAAAAAGTATCTTATG-3′ (SEQ ID NO: 1629)

Projected 21 nucleotide target sequences for each DsiRNA of Tables 2-4above and of Tables 6 and 7 below are presented in Table 5.

TABLE 5 DsiRNA Target Sequences (21mers) In HIF-1α mRNA HIF-1α-81 21 ntTarg: 5′-CCGCGCGCCCGAGCGCGCCUC-3′ (SEQ ID NO: 1630) HIF-1α-83 21 ntTarg: 5′-GCGCGCCCGAGCGCGCCUCCG-3′ (SEQ ID NO: 1631) HIF-1α-85 21 ntTarg: 5′-GCGCCCGAGCGCGCCUCCGCC-3′ (SEQ ID NO: 1632) HIF-1α-87 21 ntTarg: 5′-GCCCGAGCGCGCCUCCGCCCU-3′ (SEQ ID NO: 1633) HIF-1α-89 21 ntTarg: 5′-CCGAGCGCGCCUCCGCCCUUG-3′ (SEQ ID NO: 1634) HIF-1α-123 21 ntTarg: 5′-GCUGCCUCAGCUCCUCAGUGC-3′ (SEQ ID NO: 1635) HIF-1α-124 21 ntTarg: 5′-CUGCCUCAGCUCCUCAGUGCA-3′ (SEQ ID NO: 1636) HIF-1α-126 21 ntTarg: 5′-GCCUCAGCUCCUCAGUGCACA-3′ (SEQ ID NO: 1637) HIF-1α-130 21 ntTarg: 5′-CAGCUCCUCAGUGCACAGUGC-3′ (SEQ ID NO: 1638) HIF-1α-131 21 ntTarg: 5′-AGCUCCUCAGUGCACAGUGCU-3′ (SEQ ID NO: 1639) HIF-1α-147 21 ntTarg: 5′-GUGCUGCCUCGUCUGAGGGGA-3′ (SEQ ID NO: 1640) HIF-1α-265 21 ntTarg: 5′-GAUUGCCGCCCGCUUCUCUCU-3′ (SEQ ID NO: 1641) HIF-1α-267 21 ntTarg: 5′-UUGCCGCCCGCUUCUCUCUAG-3′ (SEQ ID NO: 1642) HIF-1α-268 21 ntTarg: 5′-UGCCGCCCGCUUCUCUCUAGU-3′ (SEQ ID NO: 1643) HIF-1α-292 21 ntTarg: 5′-ACGAGGGGUUUCCCGCCUCGC-3′ (SEQ ID NO: 1644) HIF-1α-319 21 ntTarg: 5′-ACCUCUGGACUUGCCUUUCCU-3′ (SEQ ID NO: 1645) HIF-1α-322 21 ntTarg: 5′-UCUGGACUUGCCUUUCCUUCU-3′ (SEQ ID NO: 1646) HIF-1α-324 21 ntTarg: 5′-UGGACUUGCCUUUCCUUCUCU-3′ (SEQ ID NO: 1647) HIF-1α-327 21 ntTarg: 5′-ACUUGCCUUUCCUUCUCUUCU-3′ (SEQ ID NO: 1648) HIF-1α-329 21 ntTarg: 5′-UUGCCUUUCCUUCUCUUCUCC-3′ (SEQ ID NO: 1649) HIF-1α-330 21 ntTarg: 5′-UGCCUUUCCUUCUCUUCUCCG-3′ (SEQ ID NO: 1650) HIF-1α-331 21 ntTarg: 5′-GCCUUUCCUUCUCUUCUCCGC-3′ (SEQ ID NO: 1651) HIF-1α-342 21 ntTarg: 5′-UCUUCUCCGCGUGUGGAGGGA-3′ (SEQ ID NO: 1652) HIF-1α-344 21 ntTarg: 5′-UUCUCCGCGUGUGGAGGGAGC-3′ (SEQ ID NO: 1653) HIF-1α-346 21 ntTarg: 5′-CUCCGCGUGUGGAGGGAGCCA-3′ (SEQ ID NO: 1654) HIF-1α-359 21 ntTarg: 5′-GGGAGCCAGCGCUUAGGCCGG-3′ (SEQ ID NO: 1655) HIF-1α-403 21 ntTarg: 5′-GUGAAGACAUCGCGGGGACCG-3′ (SEQ ID NO: 1656) HIF-1α-422 21 ntTarg: 5′-CGAUUCACCAUGGAGGGCGCC-3′ (SEQ ID NO: 1657) HIF-1α-427 21 ntTarg: 5′-CACCAUGGAGGGCGCCGGCGG-3′ (SEQ ID NO: 1658) HIF-1α-429 21 ntTarg: 5′-CCAUGGAGGGCGCCGGCGGCG-3′ (SEQ ID NO: 1659) HIF-1α-448 21 ntTarg: 5′-CGCGAACGACAAGAAAAAGAU-3′ (SEQ ID NO: 1660) HIF-1α-455 21 ntTarg: 5′-GACAAGAAAAAGAUAAGUUCU-3′ (SEQ ID NO: 1661) HIF-1α-469 21 ntTarg: 5′-AAGUUCUGAACGUCGAAAAGA-3′ (SEQ ID NO: 1662) HIF-1α-471 21 ntTarg: 5′-GUUCUGAACGUCGAAAAGAAA-3′ (SEQ ID NO: 1663) HIF-1α-473 21 ntTarg: 5′-UCUGAACGUCGAAAAGAAAAG-3′ (SEQ ID NO: 1664) HIF-1α-475 21 ntTarg: 5′-UGAACGUCGAAAAGAAAAGUC-3′ (SEQ ID NO: 1665) HIF-1α-525 21 ntTarg: 5′-AAGAAUCUGAAGUUUUUUAUG-3′ (SEQ ID NO: 1666) HIF-1α-528 21 ntTarg: 5′-AAUCUGAAGUUUUUUAUGAGC-3′ (SEQ ID NO: 1667) HIF-1α-530 21 ntTarg: 5′-UCUGAAGUUUUUUAUGAGCUU-3′ (SEQ ID NO: 1668) HIF-1α-532 21 ntTarg: 5′-UGAAGUUUUUUAUGAGCUUGC-3′ (SEQ ID NO: 1669) HIF-1α-534 21 ntTarg: 5′-AAGUUUUUUAUGAGCUUGCUC-3′ (SEQ ID NO: 1670) HIF-1α-536 21 ntTarg: 5′-GUUUUUUAUGAGCUUGCUCAU-3′ (SEQ ID NO: 1671) HIF-1α-538 21 ntTarg: 5′-UUUUUAUGAGCUUGCUCAUCA-3′ (SEQ ID NO: 1672) HIF-1α-540 21 ntTarg: 5′-UUUAUGAGCUUGCUCAUCAGU-3′ (SEQ ID NO: 1673) HIF-1α-542 21 ntTarg: 5′-UAUGAGCUUGCUCAUCAGUUG-3′ (SEQ ID NO: 1674) HIF-1α-544 21 ntTarg: 5′-UGAGCUUGCUCAUCAGUUGCC-3′ (SEQ ID NO: 1675) HIF-1α-546 21 ntTarg: 5′-AGCUUGCUCAUCAGUUGCCAC-3′ (SEQ ID NO: 1676) HIF-1α-548 21 ntTarg: 5′-CUUGCUCAUCAGUUGCCACUU-3′ (SEQ ID NO: 1677) HIF-1α-550 21 ntTarg: 5′-UGCUCAUCAGUUGCCACUUCC-3′ (SEQ ID NO: 1678) HIF-1α-562 21 ntTarg: 5′-GCCACUUCCACAUAAUGUGAG-3′ (SEQ ID NO: 1679) HIF-1α-642 21 ntTarg: 5′-AACUUCUGGAUGCUGGUGAUU-3′ (SEQ ID NO: 1680) HIF-1α-644 21 ntTarg: 5′-CUUCUGGAUGCUGGUGAUUUG-3′ (SEQ ID NO: 1681) HIF-1α-645 21 ntTarg: 5′-UUCUGGAUGCUGGUGAUUUGG-3′ (SEQ ID NO: 1682) HIF-1α-665 21 ntTarg: 5′-GAUAUUGAAGAUGACAUGAAA-3′ (SEQ ID NO: 1683) HIF-1α-691 21 ntTarg: 5′-GAUGAAUUGCUUUUAUUUGAA-3′ (SEQ ID NO: 1684) HIF-1α-707 21 ntTarg: 5′-UUGAAAGCCUUGGAUGGUUUU-3′ (SEQ ID NO: 1685) HIF-1α-711 21 ntTarg: 5′-AAGCCUUGGAUGGUUUUGUUA-3′ (SEQ ID NO: 1686) HIF-1α-713 21 ntTarg: 5′-GCCUUGGAUGGUUUUGUUAUG-3′ (SEQ ID NO: 1687) HIF-1α-715 21 ntTarg: 5′-CUUGGAUGGUUUUGUUAUGGU-3′ (SEQ ID NO: 1688) HIF-1α-717 21 ntTarg: 5′-UGGAUGGUUUUGUUAUGGUUC-3′ (SEQ ID NO: 1689) HIF-1α-756 21 ntTarg: 5′-UGAUUUACAUUUCUGAUAAUG-3′ (SEQ ID NO: 1690) HIF-1α-790 21 ntTarg: 5′-GGGAUUAACUCAGUUUGAACU-3′ (SEQ ID NO: 1691) HIF-1α-793 21 ntTarg: 5′-AUUAACUCAGUUUGAACUAAC-3′ (SEQ ID NO: 1692) HIF-1α-824 21 ntTarg: 5′-GUGUUUGAUUUUACUCAUCCA-3′ (SEQ ID NO: 1693) HIF-1α-826 21 ntTarg: 5′-GUUUGAUUUUACUCAUCCAUG-3′ (SEQ ID NO: 1694) HIF-1α-828 21 ntTarg: 5′-UUGAUUUUACUCAUCCAUGUG-3′ (SEQ ID NO: 1695) HIF-1α-830 21 ntTarg: 5′-GAUUUUACUCAUCCAUGUGAC-3′ (SEQ ID NO: 1696) HIF-1α-832 21 ntTarg: 5′-UUUUACUCAUCCAUGUGACCA-3′ (SEQ ID NO: 1697) HIF-1α-834 21 ntTarg: 5′-UUACUCAUCCAUGUGACCAUG-3′ (SEQ ID NO: 1698) HIF-1α-836 21 ntTarg: 5′-ACUCAUCCAUGUGACCAUGAG-3′ (SEQ ID NO: 1699) HIF-1α-838 21 ntTarg: 5′-UCAUCCAUGUGACCAUGAGGA-3′ (SEQ ID NO: 1700) HIF-1α-840 21 ntTarg: 5′-AUCCAUGUGACCAUGAGGAAA-3′ (SEQ ID NO: 1701) HIF-1α-842 21 ntTarg: 5′-CCAUGUGACCAUGAGGAAAUG-3′ (SEQ ID NO: 1702) HIF-1α-844 21 ntTarg: 5′-AUGUGACCAUGAGGAAAUGAG-3′ (SEQ ID NO: 1703) HIF-1α-846 21 ntTarg: 5′-GUGACCAUGAGGAAAUGAGAG-3′ (SEQ ID NO: 1704) HIF-1α-848 21 ntTarg: 5′-GACCAUGAGGAAAUGAGAGAA-3′ (SEQ ID NO: 1705) HIF-1α-850 21 ntTarg: 5′-CCAUGAGGAAAUGAGAGAAAU-3′ (SEQ ID NO: 1706) HIF-1α-852 21 ntTarg: 5′-AUGAGGAAAUGAGAGAAAUGC-3′ (SEQ ID NO: 1707) HIF-1α-921 21 ntTarg: 5′-AGCGAAGCUUUUUUCUCAGAA-3′ (SEQ ID NO: 1708) HIF-1α-925 21 ntTarg: 5′-AAGCUUUUUUCUCAGAAUGAA-3′ (SEQ ID NO: 1709) HIF-1α-927 21 ntTarg: 5′-GCUUUUUUCUCAGAAUGAAGU-3′ (SEQ ID NO: 1710) HIF-1α-1029 21 ntTarg: 5′-UAUAUGAUACCAACAGUAACC-3′ (SEQ ID NO: 1711) HIF-1α-1031 21 ntTarg: 5′-UAUGAUACCAACAGUAACCAA-3′ (SEQ ID NO: 1712) HIF-1α-1033 21 ntTarg: 5′-UGAUACCAACAGUAACCAACC-3′ (SEQ ID NO: 1713) HIF-1α-1035 21 ntTarg: 5′-AUACCAACAGUAACCAACCUC-3′ (SEQ ID NO: 1714) HIF-1α-1037 21 ntTarg: 5′-ACCAACAGUAACCAACCUCAG-3′ (SEQ ID NO: 1715) HIF-1α-1039 21 ntTarg: 5′-CAACAGUAACCAACCUCAGUG-3′ (SEQ ID NO: 1716) HIF-1α-1041 21 ntTarg: 5′-ACAGUAACCAACCUCAGUGUG-3′ (SEQ ID NO: 1717) HIF-1α-1043 21 ntTarg: 5′-AGUAACCAACCUCAGUGUGGG-3′ (SEQ ID NO: 1718) HIF-1α-1045 21 ntTarg: 5′-UAACCAACCUCAGUGUGGGUA-3′ (SEQ ID NO: 1719) HIF-1α-1074 21 ntTarg: 5′-CACCUAUGACCUGCUUGGUGC-3′ (SEQ ID NO: 1720) HIF-1α-1075 21 ntTarg: 5′-ACCUAUGACCUGCUUGGUGCU-3′ (SEQ ID NO: 1721) HIF-1α-1077 21 ntTarg: 5′-CUAUGACCUGCUUGGUGCUGA-3′ (SEQ ID NO: 1722) HIF-1α-1084 21 ntTarg: 5′-CUGCUUGGUGCUGAUUUGUGA-3′ (SEQ ID NO: 1723) HIF-1α-1086 21 ntTarg: 5′-GCUUGGUGCUGAUUUGUGAAC-3′ (SEQ ID NO: 1724) HIF-1α-1088 21 ntTarg: 5′-UUGGUGCUGAUUUGUGAACCC-3′ (SEQ ID NO: 1725) HIF-1α-1090 21 ntTarg: 5′-GGUGCUGAUUUGUGAACCCAU-3′ (SEQ ID NO: 1726) HIF-1α-1092 21 ntTarg: 5′-UGCUGAUUUGUGAACCCAUUC-3′ (SEQ ID NO: 1727) HIF-1α-1094 21 ntTarg: 5′-CUGAUUUGUGAACCCAUUCCU-3′ (SEQ ID NO: 1728) HIF-1α-1096 21 ntTarg: 5′-GAUUUGUGAACCCAUUCCUCA-3′ (SEQ ID NO: 1729) HIF-1α-1120 21 ntTarg: 5′-AUCAAAUAUUGAAAUUCCUUU-3′ (SEQ ID NO: 1730) HIF-1α-1122 21 ntTarg: 5′-CAAAUAUUGAAAUUCCUUUAG-3′ (SEQ ID NO: 1731) HIF-1α-1124 21 ntTarg: 5′-AAUAUUGAAAUUCCUUUAGAU-3′ (SEQ ID NO: 1732) HIF-1α-1126 21 ntTarg: 5′-UAUUGAAAUUCCUUUAGAUAG-3′ (SEQ ID NO: 1733) HIF-1α-1128 21 ntTarg: 5′-UUGAAAUUCCUUUAGAUAGCA-3′ (SEQ ID NO: 1734) HIF-1α-1130 21 ntTarg: 5′-GAAAUUCCUUUAGAUAGCAAG-3′ (SEQ ID NO: 1735) HIF-1α-1132 21 ntTarg: 5′-AAUUCCUUUAGAUAGCAAGAC-3′ (SEQ ID NO: 1736) HIF-1α-1166 21 ntTarg: 5′-CACAGCCUGGAUAUGAAAUUU-3′ (SEQ ID NO: 1737) HIF-1α-1174 21 ntTarg: 5′-GGAUAUGAAAUUUUCUUAUUG-3′ (SEQ ID NO: 1738) HIF-1α-1243 21 ntTarg: 5′-AGGCCGCUCAAUUUAUGAAUA-3′ (SEQ ID NO: 1739) HIF-1α-1245 21 ntTarg: 5′-GCCGCUCAAUUUAUGAAUAUU-3′ (SEQ ID NO: 1740) HIF-1α-1247 21 ntTarg: 5′-CGCUCAAUUUAUGAAUAUUAU-3′ (SEQ ID NO: 1741) HIF-1α-1249 21 ntTarg: 5′-CUCAAUUUAUGAAUAUUAUCA-3′ (SEQ ID NO: 1742) HIF-1α-1251 21 ntTarg: 5′-CAAUUUAUGAAUAUUAUCAUG-3′ (SEQ ID NO: 1743) HIF-1α-1253 21 ntTarg: 5′-AUUUAUGAAUAUUAUCAUGCU-3′ (SEQ ID NO: 1744) HIF-1α-1255 21 ntTarg: 5′-UUAUGAAUAUUAUCAUGCUUU-3′ (SEQ ID NO: 1745) HIF-1α-1257 21 ntTarg: 5′-AUGAAUAUUAUCAUGCUUUGG-3′ (SEQ ID NO: 1746) HIF-1α-1262 21 ntTarg: 5′-UAUUAUCAUGCUUUGGACUCU-3′ (SEQ ID NO: 1747) HIF-1α-1265 21 ntTarg: 5′-UAUCAUGCUUUGGACUCUGAU-3′ (SEQ ID NO: 1748) HIF-1α-1268 21 ntTarg: 5′-CAUGCUUUGGACUCUGAUCAU-3′ (SEQ ID NO: 1749) HIF-1α-1271 21 ntTarg: 5′-GCUUUGGACUCUGAUCAUCUG-3′ (SEQ ID NO: 1750) HIF-1α-1278 21 ntTarg: 5′-ACUCUGAUCAUCUGACCAAAA-3′ (SEQ ID NO: 1751) HIF-1α-1280 21 ntTarg: 5′-UCUGAUCAUCUGACCAAAACU-3′ (SEQ ID NO: 1752) HIF-1α-1282 21 ntTarg: 5′-UGAUCAUCUGACCAAAACUCA-3′ (SEQ ID NO: 1753) HIF-1α-1303 21 ntTarg: 5′-UCAUGAUAUGUUUACUAAAGG-3′ (SEQ ID NO: 1754) HIF-1α-1305 21 ntTarg: 5′-AUGAUAUGUUUACUAAAGGAC-3′ (SEQ ID NO: 1755) HIF-1α-1307 21 ntTarg: 5′-GAUAUGUUUACUAAAGGACAA-3′ (SEQ ID NO: 1756) HIF-1α-1309 21 ntTarg: 5′-UAUGUUUACUAAAGGACAAGU-3′ (SEQ ID NO: 1757) HIF-1α-1311 21 ntTarg: 5′-UGUUUACUAAAGGACAAGUCA-3′ (SEQ ID NO: 1758) HIF-1α-1313 21 ntTarg: 5′-UUUACUAAAGGACAAGUCACC-3′ (SEQ ID NO: 1759) HIF-1α-1315 21 ntTarg: 5′-UACUAAAGGACAAGUCACCAC-3′ (SEQ ID NO: 1760) HIF-1α-1317 21 ntTarg: 5′-CUAAAGGACAAGUCACCACAG-3′ (SEQ ID NO: 1761) HIF-1α-1319 21 ntTarg: 5′-AAAGGACAAGUCACCACAGGA-3′ (SEQ ID NO: 1762) HIF-1α-1321 21 ntTarg: 5′-AGGACAAGUCACCACAGGACA-3′ (SEQ ID NO: 1763) HIF-1α-1323 21 ntTarg: 5′-GACAAGUCACCACAGGACAGU-3′ (SEQ ID NO: 1764) HIF-1α-1325 21 ntTarg: 5′-CAAGUCACCACAGGACAGUAC-3′ (SEQ ID NO: 1765) HIF-1α-1327 21 ntTarg: 5′-AGUCACCACAGGACAGUACAG-3′ (SEQ ID NO: 1766) HIF-1α-1329 21 ntTarg: 5′-UCACCACAGGACAGUACAGGA-3′ (SEQ ID NO: 1767) HIF-1α-1331 21 ntTarg: 5′-ACCACAGGACAGUACAGGAUG-3′ (SEQ ID NO: 1768) HIF-1α-1333 21 ntTarg: 5′-CACAGGACAGUACAGGAUGCU-3′ (SEQ ID NO: 1769) HIF-1α-1335 21 ntTarg: 5′-CAGGACAGUACAGGAUGCUUG-3′ (SEQ ID NO: 1770) HIF-1α-1337 21 ntTarg: 5′-GGACAGUACAGGAUGCUUGCC-3′ (SEQ ID NO: 1771) HIF-1α-1339 21 ntTarg: 5′-ACAGUACAGGAUGCUUGCCAA-3′ (SEQ ID NO: 1772) HIF-1α-1341 21 ntTarg: 5′-AGUACAGGAUGCUUGCCAAAA-3′ (SEQ ID NO: 1773) HIF-1α-1343 21 ntTarg: 5′-UACAGGAUGCUUGCCAAAAGA-3′ (SEQ ID NO: 1774) HIF-1α-1345 21 ntTarg: 5′-CAGGAUGCUUGCCAAAAGAGG-3′ (SEQ ID NO: 1775) HIF-1α-1347 21 ntTarg: 5′-GGAUGCUUGCCAAAAGAGGUG-3′ (SEQ ID NO: 1776) HIF-1α-1349 21 ntTarg: 5′-AUGCUUGCCAAAAGAGGUGGA-3′ (SEQ ID NO: 1777) HIF-1α-1351 21 ntTarg: 5′-GCUUGCCAAAAGAGGUGGAUA-3′ (SEQ ID NO: 1778) HIF-1α-1353 21 ntTarg: 5′-UUGCCAAAAGAGGUGGAUAUG-3′ (SEQ ID NO: 1779) HIF-1α-1355 21 ntTarg: 5′-GCCAAAAGAGGUGGAUAUGUC-3′ (SEQ ID NO: 1780) HIF-1α-1357 21 ntTarg: 5′-CAAAAGAGGUGGAUAUGUCUG-3′ (SEQ ID NO: 1781) HIF-1α-1359 21 ntTarg: 5′-AAAGAGGUGGAUAUGUCUGGG-3′ (SEQ ID NO: 1782) HIF-1α-1361 21 ntTarg: 5′-AGAGGUGGAUAUGUCUGGGUU-3′ (SEQ ID NO: 1783) HIF-1α-1363 21 ntTarg: 5′-AGGUGGAUAUGUCUGGGUUGA-3′ (SEQ ID NO: 1784) HIF-1α-1365 21 ntTarg: 5′-GUGGAUAUGUCUGGGUUGAAA-3′ (SEQ ID NO: 1785) HIF-1α-1367 21 ntTarg: 5′-GGAUAUGUCUGGGUUGAAACU-3′ (SEQ ID NO: 1786) HIF-1α-1369 21 ntTarg: 5′-AUAUGUCUGGGUUGAAACUCA-3′ (SEQ ID NO: 1787) HIF-1α-1371 21 ntTarg: 5′-AUGUCUGGGUUGAAACUCAAG-3′ (SEQ ID NO: 1788) HIF-1α-1373 21 ntTarg: 5′-GUCUGGGUUGAAACUCAAGCA-3′ (SEQ ID NO: 1789) HIF-1α-1375 21 ntTarg: 5′-CUGGGUUGAAACUCAAGCAAC-3′ (SEQ ID NO: 1790) HIF-1α-1377 21 ntTarg: 5′-GGGUUGAAACUCAAGCAACUG-3′ (SEQ ID NO: 1791) HIF-1α-1379 21 ntTarg: 5′-GUUGAAACUCAAGCAACUGUC-3′ (SEQ ID NO: 1792) HIF-1α-1381 21 ntTarg: 5′-UGAAACUCAAGCAACUGUCAU-3′ (SEQ ID NO: 1793) HIF-1α-1383 21 ntTarg: 5′-AAACUCAAGCAACUGUCAUAU-3′ (SEQ ID NO: 1794) HIF-1α-1385 21 ntTarg: 5′-ACUCAAGCAACUGUCAUAUAU-3′ (SEQ ID NO: 1795) HIF-1α-1387 21 ntTarg: 5′-UCAAGCAACUGUCAUAUAUAA-3′ (SEQ ID NO: 1796) HIF-1α-1456 21 ntTarg: 5′-GAGUGGUAUUAUUCAGCACGA-3′ (SEQ ID NO: 1797) HIF-1α-1458 21 ntTarg: 5′-GUGGUAUUAUUCAGCACGACU-3′ (SEQ ID NO: 1798) HIF-1α-1460 21 ntTarg: 5′-GGUAUUAUUCAGCACGACUUG-3′ (SEQ ID NO: 1799) HIF-1α-1462 21 ntTarg: 5′-UAUUAUUCAGCACGACUUGAU-3′ (SEQ ID NO: 1800) HIF-1α-1464 21 ntTarg: 5′-UUAUUCAGCACGACUUGAUUU-3′ (SEQ ID NO: 1801) HIF-1α-1466 21 ntTarg: 5′-AUUCAGCACGACUUGAUUUUC-3′ (SEQ ID NO: 1802) HIF-1α-1468 21 ntTarg: 5′-UCAGCACGACUUGAUUUUCUC-3′ (SEQ ID NO: 1803) HIF-1α-1470 21 ntTarg: 5′-AGCACGACUUGAUUUUCUCCC-3′ (SEQ ID NO: 1804) HIF-1α-1472 21 ntTarg: 5′-CACGACUUGAUUUUCUCCCUU-3′ (SEQ ID NO: 1805) HIF-1α-1474 21 ntTarg: 5′-CGACUUGAUUUUCUCCCUUCA-3′ (SEQ ID NO: 1806) HIF-1α-1476 21 ntTarg: 5′-ACUUGAUUUUCUCCCUUCAAC-3′ (SEQ ID NO: 1807) HIF-1α-1478 21 ntTarg: 5′-UUGAUUUUCUCCCUUCAACAA-3′ (SEQ ID NO: 1808) HIF-1α-1480 21 ntTarg: 5′-GAUUUUCUCCCUUCAACAAAC-3′ (SEQ ID NO: 1809) HIF-1α-1482 21 ntTarg: 5′-UUUUCUCCCUUCAACAAACAG-3′ (SEQ ID NO: 1810) HIF-1α-1519 21 ntTarg: 5′-GGUUGAAUCUUCAGAUAUGAA-3′ (SEQ ID NO: 1811) HIF-1α-1552 21 ntTarg: 5′-AUUCACCAAAGUUGAAUCAGA-3′ (SEQ ID NO: 1812) HIF-1α-1572 21 ntTarg: 5′-AAGAUACAAGUAGCCUCUUUG-3′ (SEQ ID NO: 1813) HIF-1α-1648 21 ntTarg: 5′-CACAAUCAUAUCUUUAGAUUU-3′ (SEQ ID NO: 1814) HIF-1α-1709 21 ntTarg: 5′-GAAGUACCAUUAUAUAAUGAU-3′ (SEQ ID NO: 1815) HIF-1α-1714 21 ntTarg: 5′-ACCAUUAUAUAAUGAUGUAAU-3′ (SEQ ID NO: 1816) HIF-1α-1786 21 ntTarg: 5′-AUUACCCACCGCUGAAACGCC-3′ (SEQ ID NO: 1817) HIF-1α-1804 21 ntTarg: 5′-GCCAAAGCCACUUCGAAGUAG-3′ (SEQ ID NO: 1818) HIF-1α-1806 21 ntTarg: 5′-CAAAGCCACUUCGAAGUAGUG-3′ (SEQ ID NO: 1819) HIF-1α-1808 21 ntTarg: 5′-AAGCCACUUCGAAGUAGUGCU-3′ (SEQ ID NO: 1820) HIF-1α-1810 21 ntTarg: 5′-GCCACUUCGAAGUAGUGCUGA-3′ (SEQ ID NO: 1821) HIF-1α-1814 21 ntTarg: 5′-CUUCGAAGUAGUGCUGACCCU-3′ (SEQ ID NO: 1822) HIF-1α-1845 21 ntTarg: 5′-AAGAAGUUGCAUUAAAAUUAG-3′ (SEQ ID NO: 1823) HIF-1α-1936 21 ntTarg: 5′-CGAUGGAAGCACUAGACAAAG-3′ (SEQ ID NO: 1824) HIF-1α-1938 21 ntTarg: 5′-AUGGAAGCACUAGACAAAGUU-3′ (SEQ ID NO: 1825) HIF-1α-1940 21 ntTarg: 5′-GGAAGCACUAGACAAAGUUCA-3′ (SEQ ID NO: 1826) HIF-1α-1942 21 ntTarg: 5′-AAGCACUAGACAAAGUUCACC-3′ (SEQ ID NO: 1827) HIF-1α-1944 21 ntTarg: 5′-GCACUAGACAAAGUUCACCUG-3′ (SEQ ID NO: 1828) HIF-1α-1946 21 ntTarg: 5′-ACUAGACAAAGUUCACCUGAG-3′ (SEQ ID NO: 1829) HIF-1α-1977 21 ntTarg: 5′-CCAGUGAAUAUUGUUUUUAUG-3′ (SEQ ID NO: 1830) HIF-1α-1985 21 ntTarg: 5′-UAUUGUUUUUAUGUGGAUAGU-3′ (SEQ ID NO: 1831) HIF-1α-2034 21 ntTarg: 5′-UGGUAGAAAAACUUUUUGCUG-3′ (SEQ ID NO: 1832) HIF-1α-2116 21 ntTarg: 5′-AGCUCCCUAUAUCCCAAUGGA-3′ (SEQ ID NO: 1833) HIF-1α-2118 21 ntTarg: 5′-CUCCCUAUAUCCCAAUGGAUG-3′ (SEQ ID NO: 1834) HIF-1α-2120 21 ntTarg: 5′-CCCUAUAUCCCAAUGGAUGAU-3′ (SEQ ID NO: 1835) HIF-1α-2122 21 ntTarg: 5′-CUAUAUCCCAAUGGAUGAUGA-3′ (SEQ ID NO: 1836) HIF-1α-2161 21 ntTarg: 5′-CGAUCAGUUGUCACCAUUAGA-3′ (SEQ ID NO: 1837) HIF-1α-2185 21 ntTarg: 5′-CAGUUCCGCAAGCCCUGAAAG-3′ (SEQ ID NO: 1838) HIF-1α-2187 21 ntTarg: 5′-GUUCCGCAAGCCCUGAAAGCG-3′ (SEQ ID NO: 1839) HIF-1α-2290 21 ntTarg: 5′-CACUGAUGAAUUAAAAACAGU-3′ (SEQ ID NO: 1840) HIF-1α-2326 21 ntTarg: 5′-GGAAGACAUUAAAAUAUUGAU-3′ (SEQ ID NO: 1841) HIF-1α-2452 21 ntTarg: 5′-AGGAGUCAUAGAACAGACAGA-3′ (SEQ ID NO: 1842) HIF-1α-2555 21 ntTarg: 5′-AAGAUACUAGCUUUGCAGAAU-3′ (SEQ ID NO: 1843) HIF-1α-2577 21 ntTarg: 5′-CUCAGAGAAAGCGAAAAAUGG-3′ (SEQ ID NO: 1844) HIF-1α-2584 21 ntTarg: 5′-AAAGCGAAAAAUGGAACAUGA-3′ (SEQ ID NO: 1845) HIF-1α-2586 21 ntTarg: 5′-AGCGAAAAAUGGAACAUGAUG-3′ (SEQ ID NO: 1846) HIF-1α-2618 21 ntTarg: 5′-CAAGCAGUAGGAAUUGGAACA-3′ (SEQ ID NO: 1847) HIF-1α-2705 21 ntTarg: 5′-AAAUCUAGUGAACAGAAUGGA-3′ (SEQ ID NO: 1848) HIF-1α-2730 21 ntTarg: 5′-AGCAAAAGACAAUUAUUUUAA-3′ (SEQ ID NO: 1849) HIF-1α-2796 21 ntTarg: 5′-AAAGUGGAUUACCACAGCUGA-3′ (SEQ ID NO: 1850) HIF-1α-2798 21 ntTarg: 5′-AGUGGAUUACCACAGCUGACC-3′ (SEQ ID NO: 1851) HIF-1α-2800 21 ntTarg: 5′-UGGAUUACCACAGCUGACCAG-3′ (SEQ ID NO: 1852) HIF-1α-2802 21 ntTarg: 5′-GAUUACCACAGCUGACCAGUU-3′ (SEQ ID NO: 1853) HIF-1α-2823 21 ntTarg: 5′-AUGAUUGUGAAGUUAAUGCUC-3′ (SEQ ID NO: 1854) HIF-1α-2844 21 ntTarg: 5′-CUAUACAAGGCAGCAGAAACC-3′ (SEQ ID NO: 1855) HIF-1α-2846 21 ntTarg: 5′-AUACAAGGCAGCAGAAACCUA-3′ (SEQ ID NO: 1856) HIF-1α-2848 21 ntTarg: 5′-ACAAGGCAGCAGAAACCUACU-3′ (SEQ ID NO: 1857) HIF-1α-2850 21 ntTarg: 5′-AAGGCAGCAGAAACCUACUGC-3′ (SEQ ID NO: 1858) HIF-1α-2852 21 ntTarg: 5′-GGCAGCAGAAACCUACUGCAG-3′ (SEQ ID NO: 1859) HIF-1α-2854 21 ntTarg: 5′-CAGCAGAAACCUACUGCAGGG-3′ (SEQ ID NO: 1860) HIF-1α-2856 21 ntTarg: 5′-GCAGAAACCUACUGCAGGGUG-3′ (SEQ ID NO: 1861) HIF-1α-2858 21 ntTarg: 5′-AGAAACCUACUGCAGGGUGAA-3′ (SEQ ID NO: 1862) HIF-1α-2860 21 ntTarg: 5′-AAACCUACUGCAGGGUGAAGA-3′ (SEQ ID NO: 1863) HIF-1α-2862 21 ntTarg: 5′-ACCUACUGCAGGGUGAAGAAU-3′ (SEQ ID NO: 1864) HIF-1α-2864 21 ntTarg: 5′-CUACUGCAGGGUGAAGAAUUA-3′ (SEQ ID NO: 1865) HIF-1α-2866 21 ntTarg: 5′-ACUGCAGGGUGAAGAAUUACU-3′ (SEQ ID NO: 1866) HIF-1α-2868 21 ntTarg: 5′-UGCAGGGUGAAGAAUUACUCA-3′ (SEQ ID NO: 1867) HIF-1α-2870 21 ntTarg: 5′-CAGGGUGAAGAAUUACUCAGA-3′ (SEQ ID NO: 1868) HIF-1α-2872 21 ntTarg: 5′-GGGUGAAGAAUUACUCAGAGC-3′ (SEQ ID NO: 1869) HIF-1α-2874 21 ntTarg: 5′-GUGAAGAAUUACUCAGAGCUU-3′ (SEQ ID NO: 1870) HIF-1α-2876 21 ntTarg: 5′-GAAGAAUUACUCAGAGCUUUG-3′ (SEQ ID NO: 1871) HIF-1α-2878 21 ntTarg: 5′-AGAAUUACUCAGAGCUUUGGA-3′ (SEQ ID NO: 1872) HIF-1α-2880 21 ntTarg: 5′-AAUUACUCAGAGCUUUGGAUC-3′ (SEQ ID NO: 1873) HIF-1α-2882 21 ntTarg: 5′-UUACUCAGAGCUUUGGAUCAA-3′ (SEQ ID NO: 1874) HIF-1α-2884 21 ntTarg: 5′-ACUCAGAGCUUUGGAUCAAGU-3′ (SEQ ID NO: 1875) HIF-1α-2886 21 ntTarg: 5′-UCAGAGCUUUGGAUCAAGUUA-3′ (SEQ ID NO: 1876) HIF-1α-2888 21 ntTarg: 5′-AGAGCUUUGGAUCAAGUUAAC-3′ (SEQ ID NO: 1877) HIF-1α-2890 21 ntTarg: 5′-AGCUUUGGAUCAAGUUAACUG-3′ (SEQ ID NO: 1878) HIF-1α-2892 21 ntTarg: 5′-CUUUGGAUCAAGUUAACUGAG-3′ (SEQ ID NO: 1879) HIF-1α-2895 21 ntTarg: 5′-UGGAUCAAGUUAACUGAGCUU-3′ (SEQ ID NO: 1880) HIF-1α-2906 21 ntTarg: 5′-AACUGAGCUUUUUCUUAAUUU-3′ (SEQ ID NO: 1881) HIF-1α-2910 21 ntTarg: 5′-GAGCUUUUUCUUAAUUUCAUU-3′ (SEQ ID NO: 1882) HIF-1α-2919 21 ntTarg: 5′-CUUAAUUUCAUUCCUUUUUUU-3′ (SEQ ID NO: 1883) HIF-1α-2925 21 ntTarg: 5′-UUCAUUCCUUUUUUUGGACAC-3′ (SEQ ID NO: 1884) HIF-1α-2933 21 ntTarg: 5′-UUUUUUUGGACACUGGUGGCU-3′ (SEQ ID NO: 1885) HIF-1α-2935 21 ntTarg: 5′-UUUUUGGACACUGGUGGCUCA-3′ (SEQ ID NO: 1886) HIF-1α-2963 21 ntTarg: 5′-AAGCAGUCUAUUUAUAUUUUC-3′ (SEQ ID NO: 1887) HIF-1α-2965 21 ntTarg: 5′-GCAGUCUAUUUAUAUUUUCUA-3′ (SEQ ID NO: 1888) HIF-1α-2970 21 ntTarg: 5′-CUAUUUAUAUUUUCUACAUCU-3′ (SEQ ID NO: 1889) HIF-1α-2986 21 ntTarg: 5′-CAUCUAAUUUUAGAAGCCUGG-3′ (SEQ ID NO: 1890) HIF-1α-2988 21 ntTarg: 5′-UCUAAUUUUAGAAGCCUGGCU-3′ (SEQ ID NO: 1891) HIF-1α-2990 21 ntTarg: 5′-UAAUUUUAGAAGCCUGGCUAC-3′ (SEQ ID NO: 1892) HIF-1α-2992 21 ntTarg: 5′-AUUUUAGAAGCCUGGCUACAA-3′ (SEQ ID NO: 1893) HIF-1α-2994 21 ntTarg: 5′-UUUAGAAGCCUGGCUACAAUA-3′ (SEQ ID NO: 1894) HIF-1α-2996 21 ntTarg: 5′-UAGAAGCCUGGCUACAAUACU-3′ (SEQ ID NO: 1895) HIF-1α-2998 21 ntTarg: 5′-GAAGCCUGGCUACAAUACUGC-3′ (SEQ ID NO: 1896) HIF-1α-3000 21 ntTarg: 5′-AGCCUGGCUACAAUACUGCAC-3′ (SEQ ID NO: 1897) HIF-1α-3002 21 ntTarg: 5′-CCUGGCUACAAUACUGCACAA-3′ (SEQ ID NO: 1898) HIF-1α-3004 21 ntTarg: 5′-UGGCUACAAUACUGCACAAAC-3′ (SEQ ID NO: 1899) HIF-1α-3055 21 ntTarg: 5′-CUUAAUUUACAUUAAUGCUCU-3′ (SEQ ID NO: 1900) HIF-1α-3065 21 ntTarg: 5′-AUUAAUGCUCUUUUUUAGUAU-3′ (SEQ ID NO: 1901) HIF-1α-3067 21 ntTarg: 5′-UAAUGCUCUUUUUUAGUAUGU-3′ (SEQ ID NO: 1902) HIF-1α-3068 21 ntTarg: 5′-AAUGCUCUUUUUUAGUAUGUU-3′ (SEQ ID NO: 1903) HIF-1α-3077 21 ntTarg: 5′-UUUUAGUAUGUUCUUUAAUGC-3′ (SEQ ID NO: 1904) HIF-1α-3081 21 ntTarg: 5′-AGUAUGUUCUUUAAUGCUGGA-3′ (SEQ ID NO: 1905) HIF-1α-3088 21 ntTarg: 5′-UCUUUAAUGCUGGAUCACAGA-3′ (SEQ ID NO: 1906) HIF-1α-3093 21 ntTarg: 5′-AAUGCUGGAUCACAGACAGCU-3′ (SEQ ID NO: 1907) HIF-1α-3110 21 ntTarg: 5′-AGCUCAUUUUCUCAGUUUUUU-3′ (SEQ ID NO: 1908) HIF-1α-3167 21 ntTarg: 5′-AAAAAAUGCACCUUUUUAUUU-3′ (SEQ ID NO: 1909) HIF-1α-3169 21 ntTarg: 5′-AAAAUGCACCUUUUUAUUUAU-3′ (SEQ ID NO: 1910) HIF-1α-3171 21 ntTarg: 5′-AAUGCACCUUUUUAUUUAUUU-3′ (SEQ ID NO: 1911) HIF-1α-3173 21 ntTarg: 5′-UGCACCUUUUUAUUUAUUUAU-3′ (SEQ ID NO: 1912) HIF-1α-3175 21 ntTarg: 5′-CACCUUUUUAUUUAUUUAUUU-3′ (SEQ ID NO: 1913) HIF-1α-3177 21 ntTarg: 5′-CCUUUUUAUUUAUUUAUUUUU-3′ (SEQ ID NO: 1914) HIF-1α-3179 21 ntTarg: 5′-UUUUUAUUUAUUUAUUUUUGG-3′ (SEQ ID NO: 1915) HIF-1α-3215 21 ntTarg: 5′-CUUUUUCGAAUUAUUUUUAAG-3′ (SEQ ID NO: 1916) HIF-1α-3241 21 ntTarg: 5′-GCCAAUAUAAUUUUUGUAAGA-3′ (SEQ ID NO: 1917) HIF-1α-3274 21 ntTarg: 5′-UUCAUCAUGAUCAUAGGCAGU-3′ (SEQ ID NO: 1918) HIF-1α-3276 21 ntTarg: 5′-CAUCAUGAUCAUAGGCAGUUG-3′ (SEQ ID NO: 1919) HIF-1α-3278 21 ntTarg: 5′-UCAUGAUCAUAGGCAGUUGAA-3′ (SEQ ID NO: 1920) HIF-1α-3280 21 ntTarg: 5′-AUGAUCAUAGGCAGUUGAAAA-3′ (SEQ ID NO: 1921) HIF-1α-3292 21 ntTarg: 5′-AGUUGAAAAAUUUUUACACCU-3′ (SEQ ID NO: 1922) HIF-1α-3310 21 ntTarg: 5′-CCUUUUUUUUCACAUUUUACA-3′ (SEQ ID NO: 1923) HIF-1α-3358 21 ntTarg: 5′-GUGGUAGCCACAAUUGCACAA-3′ (SEQ ID NO: 1924) HIF-1α-3360 21 ntTarg: 5′-GGUAGCCACAAUUGCACAAUA-3′ (SEQ ID NO: 1925) HIF-1α-3362 21 ntTarg: 5′-UAGCCACAAUUGCACAAUAUA-3′ (SEQ ID NO: 1926) HIF-1α-3364 21 ntTarg: 5′-GCCACAAUUGCACAAUAUAUU-3′ (SEQ ID NO: 1927) HIF-1α-3366 21 ntTarg: 5′-CACAAUUGCACAAUAUAUUUU-3′ (SEQ ID NO: 1928) HIF-1α-3368 21 ntTarg: 5′-CAAUUGCACAAUAUAUUUUCU-3′ (SEQ ID NO: 1929) HIF-1α-3374 21 ntTarg: 5′-CACAAUAUAUUUUCUUAAAAA-3′ (SEQ ID NO: 1930) HIF-1α-3425 21 ntTarg: 5′-GCGUUUAUAAAACUAGUUUUU-3′ (SEQ ID NO: 1931) HIF-1α-3426 21 ntTarg: 5′-CGUUUAUAAAACUAGUUUUUA-3′ (SEQ ID NO: 1932) HIF-1α-3428 21 ntTarg: 5′-UUUAUAAAACUAGUUUUUAAG-3′ (SEQ ID NO: 1933) HIF-1α-3430 21 ntTarg: 5′-UAUAAAACUAGUUUUUAAGAA-3′ (SEQ ID NO: 1934) HIF-1α-3442 21 ntTarg: 5′-UUUUAAGAAGAAAUUUUUUUU-3′ (SEQ ID NO: 1935) HIF-1α-3448 21 ntTarg: 5′-GAAGAAAUUUUUUUUGGCCUA-3′ (SEQ ID NO: 1936) HIF-1α-3450 21 ntTarg: 5′-AGAAAUUUUUUUUGGCCUAUG-3′ (SEQ ID NO: 1937) HIF-1α-3465 21 ntTarg: 5′-CCUAUGAAAUUGUUAAACCUG-3′ (SEQ ID NO: 1938) HIF-1α-3493 21 ntTarg: 5′-ACAUUGUUAAUCAUAUAAUAA-3′ (SEQ ID NO: 1939) HIF-1α-3529 21 ntTarg: 5′-GUAUGGUUUAUUAUUUAAAUG-3′ (SEQ ID NO: 1940) HIF-1α-3546 21 ntTarg: 5′-AAUGGGUAAAGCCAUUUACAU-3′ (SEQ ID NO: 1941) HIF-1α-3557 21 ntTarg: 5′-CCAUUUACAUAAUAUAGAAAG-3′ (SEQ ID NO: 1942) HIF-1α-3592 21 ntTarg: 5′-AGAAGGUAUGUGGCAUUUAUU-3′ (SEQ ID NO: 1943) HIF-1α-3594 21 ntTarg: 5′-AAGGUAUGUGGCAUUUAUUUG-3′ (SEQ ID NO: 1944) HIF-1α-3596 21 ntTarg: 5′-GGUAUGUGGCAUUUAUUUGGA-3′ (SEQ ID NO: 1945) HIF-1α-3598 21 ntTarg: 5′-UAUGUGGCAUUUAUUUGGAUA-3′ (SEQ ID NO: 1946) HIF-1α-3600 21 ntTarg: 5′-UGUGGCAUUUAUUUGGAUAAA-3′ (SEQ ID NO: 1947) HIF-1α-3602 21 ntTarg: 5′-UGGCAUUUAUUUGGAUAAAAU-3′ (SEQ ID NO: 1948) HIF-1α-3604 21 ntTarg: 5′-GCAUUUAUUUGGAUAAAAUUC-3′ (SEQ ID NO: 1949) HIF-1α-3606 21 ntTarg: 5′-AUUUAUUUGGAUAAAAUUCUC-3′ (SEQ ID NO: 1950) HIF-1α-3608 21 ntTarg: 5′-UUAUUUGGAUAAAAUUCUCAA-3′ (SEQ ID NO: 1951) HIF-1α-3608 21 ntTarg: 5′-UUAUUUGGAUAAAAUUCUCAA-3′ (SEQ ID NO: 1952) HIF-1α-3610 21 ntTarg: 5′-AUUUGGAUAAAAUUCUCAAUU-3′ (SEQ ID NO: 1953) HIF-1α-3612 21 ntTarg: 5′-UUGGAUAAAAUUCUCAAUUCA-3′ (SEQ ID NO: 1954) HIF-1α-3614 21 ntTarg: 5′-GGAUAAAAUUCUCAAUUCAGA-3′ (SEQ ID NO: 1955) HIF-1α-3616 21 ntTarg: 5′-AUAAAAUUCUCAAUUCAGAGA-3′ (SEQ ID NO: 1956) HIF-1α-3640 21 ntTarg: 5′-CAUCUGAUGUUUCUAUAGUCA-3′ (SEQ ID NO: 1957) HIF-1α-3646 21 ntTarg: 5′-AUGUUUCUAUAGUCACUUUGC-3′ (SEQ ID NO: 1958) HIF-1α-3651 21 ntTarg: 5′-UCUAUAGUCACUUUGCCAGCU-3′ (SEQ ID NO: 1959) HIF-1α-3670 21 ntTarg: 5′-CUCAAAAGAAAACAAUACCCU-3′ (SEQ ID NO: 1960) HIF-1α-3743 21 ntTarg: 5′-UGUUCUGCCUACCCUGUUGGU-3′ (SEQ ID NO: 1961) HIF-1α-3745 21 ntTarg: 5′-UUCUGCCUACCCUGUUGGUAU-3′ (SEQ ID NO: 1962) HIF-1α-3746 21 ntTarg: 5′-UCUGCCUACCCUGUUGGUAUA-3′ (SEQ ID NO: 1963) HIF-1α-3748 21 ntTarg: 5′-UGCCUACCCUGUUGGUAUAAA-3′ (SEQ ID NO: 1964) HIF-1α-3749 21 ntTarg: 5′-GCCUACCCUGUUGGUAUAAAG-3′ (SEQ ID NO: 1965) HIF-1α-3754 21 ntTarg: 5′-CCCUGUUGGUAUAAAGAUAUU-3′ (SEQ ID NO: 1966) HIF-1α-3757 21 ntTarg: 5′-UGUUGGUAUAAAGAUAUUUUG-3′ (SEQ ID NO: 1967) HIF-1α-3791 21 ntTarg: 5′-CAAGAAAAAAAAAAUCAUGCA-3′ (SEQ ID NO: 1968) HIF-1α-3830 21 ntTarg: 5′-AGUAUGUUAAUUUGCUCAAAA-3′ (SEQ ID NO: 1969) HIF-1α-3861 21 ntTarg: 5′-GAUUUUAUGCACUUUGUCGCU-3′ (SEQ ID NO: 1970) HIF-1α-3863 21 ntTarg: 5′-UUUUAUGCACUUUGUCGCUAU-3′ (SEQ ID NO: 1971) HIF-1α-3865 21 ntTarg: 5′-UUAUGCACUUUGUCGCUAUUA-3′ (SEQ ID NO: 1972) HIF-1α-3867 21 ntTarg: 5′-AUGCACUUUGUCGCUAUUAAC-3′ (SEQ ID NO: 1973) HIF-1α-3869 21 ntTarg: 5′-GCACUUUGUCGCUAUUAACAU-3′ (SEQ ID NO: 1974) HIF-1α-3871 21 ntTarg: 5′-ACUUUGUCGCUAUUAACAUCC-3′ (SEQ ID NO: 1975) HIF-1α-3873 21 ntTarg: 5′-UUUGUCGCUAUUAACAUCCUU-3′ (SEQ ID NO: 1976) HIF-1α-3875 21 ntTarg: 5′-UGUCGCUAUUAACAUCCUUUU-3′ (SEQ ID NO: 1977) HIF-1α-3877 21 ntTarg: 5′-UCGCUAUUAACAUCCUUUUUU-3′ (SEQ ID NO: 1978) HIF-1α-3880 21 ntTarg: 5′-CUAUUAACAUCCUUUUUUUCA-3′ (SEQ ID NO: 1979) HIF-1α-3916 21 ntTarg: 5′-UUGAGUAAUUUUAGAAGCAUU-3′ (SEQ ID NO: 1980) HIF-1α-3918 21 ntTarg: 5′-GAGUAAUUUUAGAAGCAUUAU-3′ (SEQ ID NO: 1981) HIF-1α-3920 21 ntTarg: 5′-GUAAUUUUAGAAGCAUUAUUU-3′ (SEQ ID NO: 1982) HIF-1α-3922 21 ntTarg: 5′-AAUUUUAGAAGCAUUAUUUUA-3′ (SEQ ID NO: 1983) HIF-1α-3924 21 ntTarg: 5′-UUUUAGAAGCAUUAUUUUAGG-3′ (SEQ ID NO: 1984) HIF-1α-3926 21 ntTarg: 5′-UUAGAAGCAUUAUUUUAGGAA-3′ (SEQ ID NO: 1985) HIF-1α-3928 21 ntTarg: 5′-AGAAGCAUUAUUUUAGGAAUA-3′ (SEQ ID NO: 1986) HIF-1α-3930 21 ntTarg: 5′-AAGCAUUAUUUUAGGAAUAUA-3′ (SEQ ID NO: 1987) HIF-1α-3961 21 ntTarg: 5′-AGUAAAUAUCUUGUUUUUUCU-3′ (SEQ ID NO: 1988) HIF-1α-3980 21 ntTarg: 5′-CUAUGUACAUUGUACAAAUUU-3′ (SEQ ID NO: 1989) HIF-1α-3999 21 ntTarg: 5′-UUUUCAUUCCUUUUGCUCUUU-3′ (SEQ ID NO: 1990) HIF-1α-4000 21 ntTarg: 5′-UUUCAUUCCUUUUGCUCUUUG-3′ (SEQ ID NO: 1991) HIF-1α-4001 21 ntTarg: 5′-UUCAUUCCUUUUGCUCUUUGU-3′ (SEQ ID NO: 1992) HIF-1α-4003 21 ntTarg: 5′-CAUUCCUUUUGCUCUUUGUGG-3′ (SEQ ID NO: 1993) HIF-1α-4004 21 ntTarg: 5′-AUUCCUUUUGCUCUUUGUGGU-3′ (SEQ ID NO: 1994) HIF-1α-4005 21 ntTarg: 5′-UUCCUUUUGCUCUUUGUGGUU-3′ (SEQ ID NO: 1995) HIF-1α-4006 21 ntTarg: 5′-UCCUUUUGCUCUUUGUGGUUG-3′ (SEQ ID NO: 1996) HIF-1α-4007 21 ntTarg: 5′-CCUUUUGCUCUUUGUGGUUGG-3′ (SEQ ID NO: 1997) HIF-1α-4008 21 ntTarg: 5′-CUUUUGCUCUUUGUGGUUGGA-3′ (SEQ ID NO: 1998) HIF-1α-4009 21 ntTarg: 5′-UUUUGCUCUUUGUGGUUGGAU-3′ (SEQ ID NO: 1999) HIF-1α-4010 21 ntTarg: 5′-UUUGCUCUUUGUGGUUGGAUC-3′ (SEQ ID NO: 2000) HIF-1α-4012 21 ntTarg: 5′-UGCUCUUUGUGGUUGGAUCUA-3′ (SEQ ID NO: 2001) HIF-1α-4055 21 ntTarg: 5′-ACAUCAAAUAAACAUCUUCUG-3′ (SEQ ID NO: 2002) HIF-1α-4057 21 ntTarg: 5′-AUCAAAUAAACAUCUUCUGUG-3′ (SEQ ID NO: 2003) HIF-1α-4059 21 ntTarg: 5′-CAAAUAAACAUCUUCUGUGGA-3′ (SEQ ID NO: 2004) HIF-1α-4061 21 ntTarg: 5′-AAUAAACAUCUUCUGUGGACC-3′ (SEQ ID NO: 2005) HIF-1α-4063 21 ntTarg: 5′-UAAACAUCUUCUGUGGACCAG-3′ (SEQ ID NO: 2006) HIF-1α-4065 21 ntTarg: 5′-AACAUCUUCUGUGGACCAGGC-3′ (SEQ ID NO: 2007) HIF-1α-m38 21 ntTarg: 5′-GCCCGCGGGCGCGCGCGUUGG-3′ (SEQ ID NO: 2008) HIF-1α-m40 21 ntTarg: 5′-CCGCGGGCGCGCGCGUUGGGU-3′ (SEQ ID NO: 2009) HIF-1α-m41 21 ntTarg: 5′-CGCGGGCGCGCGCGUUGGGUG-3′ (SEQ ID NO: 2010) HIF-1α-m42 21 ntTarg: 5′-GCGGGCGCGCGCGUUGGGUGC-3′ (SEQ ID NO: 2011) HIF-1α-m43 21 ntTarg: 5′-CGGGCGCGCGCGUUGGGUGCU-3′ (SEQ ID NO: 2012) HIF-1α-m44 21 ntTarg: 5′-GGGCGCGCGCGUUGGGUGCUG-3′ (SEQ ID NO: 2013) HIF-1α-m45 21 ntTarg: 5′-GGCGCGCGCGUUGGGUGCUGA-3′ (SEQ ID NO: 2014) HIF-1α-m46 21 ntTarg: 5′-GCGCGCGCGUUGGGUGCUGAG-3′ (SEQ ID NO: 2015) HIF-1α-m47 21 ntTarg: 5′-CGCGCGCGUUGGGUGCUGAGC-3′ (SEQ ID NO: 2016) HIF-1α-m49 21 ntTarg: 5′-CGCGCGUUGGGUGCUGAGCGG-3′ (SEQ ID NO: 2017) HIF-1α-m50 21 ntTarg: 5′-GCGCGUUGGGUGCUGAGCGGG-3′ (SEQ ID NO: 2018) HIF-1α-m51 21 ntTarg: 5′-CGCGUUGGGUGCUGAGCGGGC-3′ (SEQ ID NO: 2019) HIF-1α-m52 21 ntTarg: 5′-GCGUUGGGUGCUGAGCGGGCG-3′ (SEQ ID NO: 2020) HIF-1α-m53 21 ntTarg: 5′-CGUUGGGUGCUGAGCGGGCGC-3′ (SEQ ID NO: 2021) HIF-1α-m55 21 ntTarg: 5′-UUGGGUGCUGAGCGGGCGCGC-3′ (SEQ ID NO: 2022) HIF-1α-m97 21 ntTarg: 5′-CCCUCGCCGCGCGCCCGAGCG-3′ (SEQ ID NO: 2023) HIF-1α-m98 21 ntTarg: 5′-CCUCGCCGCGCGCCCGAGCGC-3′ (SEQ ID NO: 2024) HIF-1α-m99 21 ntTarg: 5′-CUCGCCGCGCGCCCGAGCGCG-3′ (SEQ ID NO: 2025) HIF-1α-m100 21 ntTarg: 5′-UCGCCGCGCGCCCGAGCGCGC-3′ (SEQ ID NO: 2026) HIF-1α-m139 21 ntTarg: 5′-CCUGCCGCUGCUUCAGCGCCU-3′ (SEQ ID NO: 2027) HIF-1α-m141 21 ntTarg: 5′-UGCCGCUGCUUCAGCGCCUCA-3′ (SEQ ID NO: 2028) HIF-1α-m145 21 ntTarg: 5′-GCUGCUUCAGCGCCUCAGUGC-3′ (SEQ ID NO: 2029) HIF-1α-m146 21 ntTarg: 5′-CUGCUUCAGCGCCUCAGUGCA-3′ (SEQ ID NO: 2030) HIF-1α-m148 21 ntTarg: 5′-GCUUCAGCGCCUCAGUGCACA-3′ (SEQ ID NO: 2031) HIF-1α-m152 21 ntTarg: 5′-CAGCGCCUCAGUGCACAGAGC-3′ (SEQ ID NO: 2032) HIF-1α-m271 21 ntTarg: 5′-GAGCCGGAGCUCAGCGAGCGC-3′ (SEQ ID NO: 2033) HIF-1α-m277 21 ntTarg: 5′-GAGCUCAGCGAGCGCAGCCUG-3′ (SEQ ID NO: 2034) HIF-1α-m282 21 ntTarg: 5′-CAGCGAGCGCAGCCUGCAGCU-3′ (SEQ ID NO: 2035) HIF-1α-m283 21 ntTarg: 5′-AGCGAGCGCAGCCUGCAGCUC-3′ (SEQ ID NO: 2036) HIF-1α-m284 21 ntTarg: 5′-GCGAGCGCAGCCUGCAGCUCC-3′ (SEQ ID NO: 2037) HIF-1α-m286 21 ntTarg: 5′-GAGCGCAGCCUGCAGCUCCCG-3′ (SEQ ID NO: 2038) HIF-1α-m289 21 ntTarg: 5′-CGCAGCCUGCAGCUCCCGCCU-3′ (SEQ ID NO: 2039) HIF-1α-m348 21 ntTarg: 5′-UGGACUUGUCUCUUUCUCCGC-3′ (SEQ ID NO: 2040) HIF-1α-m350 21 ntTarg: 5′-GACUUGUCUCUUUCUCCGCGC-3′ (SEQ ID NO: 2041) HIF-1α-m352 21 ntTarg: 5′-CUUGUCUCUUUCUCCGCGCGC-3′ (SEQ ID NO: 2042) HIF-1α-m353 21 ntTarg: 5′-UUGUCUCUUUCUCCGCGCGCG-3′ (SEQ ID NO: 2043) HIF-1α-m354 21 ntTarg: 5′-UGUCUCUUUCUCCGCGCGCGC-3′ (SEQ ID NO: 2044) HIF-1α-m357 21 ntTarg: 5′-CUCUUUCUCCGCGCGCGCGGA-3′ (SEQ ID NO: 2045) HIF-1α-m359 21 ntTarg: 5′-CUUUCUCCGCGCGCGCGGACA-3′ (SEQ ID NO: 2046) HIF-1α-m365 21 ntTarg: 5′-CCGCGCGCGCGGACAGAGCCG-3′ (SEQ ID NO: 2047) HIF-1α-m597 21 ntTarg: 5′-GUGAGCUCACAUCUUGAUAAA-3′ (SEQ ID NO: 2048) HIF-1α-m600 21 ntTarg: 5′-AGCUCACAUCUUGAUAAAGCU-3′ (SEQ ID NO: 2049) HIF-1α-m712 21 ntTarg: 5′-UGGACUGUUUUUAUCUGAAAG-3′ (SEQ ID NO: 2050) HIF-1α-m1093 21 ntTarg: 5′-CACCCAUGACGUGCUUGGUGC-3′ (SEQ ID NO: 2051) HIF-1α-m1593 21 ntTarg: 5′-GAUACAAGCUGCCUUUUUGAU-3′ (SEQ ID NO: 2052) HIF-1α-m1595 21 ntTarg: 5′-UACAAGCUGCCUUUUUGAUAA-3′ (SEQ ID NO: 2053) HIF-1α-m1596 21 ntTarg: 5′-ACAAGCUGCCUUUUUGAUAAG-3′ (SEQ ID NO: 2054) HIF-1α-m1599 21 ntTarg: 5′-AGCUGCCUUUUUGAUAAGCUU-3′ (SEQ ID NO: 2055) HIF-1α-m1632 21 ntTarg: 5′-GAUGCUCUCACUCUGCUGGCU-3′ (SEQ ID NO: 2056) HIF-1α-m1633 21 ntTarg: 5′-AUGCUCUCACUCUGCUGGCUC-3′ (SEQ ID NO: 2057) HIF-1α-m1634 21 ntTarg: 5′-UGCUCUCACUCUGCUGGCUCC-3′ (SEQ ID NO: 2058) HIF-1α-m1642 21 ntTarg: 5′-CUCUGCUGGCUCCAGCUGCCG-3′ (SEQ ID NO: 2059) HIF-1α-m1830 21 ntTarg: 5′-CUUCGAAGUAGUGCUGAUCCU-3′ (SEQ ID NO: 2060) HIF-1α-m2041 21 ntTarg: 5′-AAUAUUGCUUUGAUGUGGAUA-3′ (SEQ ID NO: 2061) HIF-1α-m2043 21 ntTarg: 5′-UAUUGCUUUGAUGUGGAUAGC-3′ (SEQ ID NO: 2062) HIF-1α-m2045 21 ntTarg: 5′-UUGCUUUGAUGUGGAUAGCGA-3′ (SEQ ID NO: 2063) HIF-1α-m2650 21 ntTarg: 5′-AUGAUGGCUCCCUUUUUCAAG-3′ (SEQ ID NO: 2064) HIF-1α-m3030 21 ntTarg: 5′-GUUUCUGUUGGUUAUUUUUGG-3′ (SEQ ID NO: 2065) HIF-1α-m3557 21 ntTarg: 5′-UGUUAAGCCUGGAUCAUGAAG-3′ (SEQ ID NO: 2066) HIF-1α-m3562 21 ntTarg: 5′-AGCCUGGAUCAUGAAGCUGUU-3′ (SEQ ID NO: 2067) HIF-1α-m3576 21 ntTarg: 5′-AGCUGUUGAUCUUAUAAUGAU-3′ (SEQ ID NO: 2068) HIF-1α-m3592 21 ntTarg: 5′-AUGAUUCUUAAACUGUAUGGU-3′ (SEQ ID NO: 2069) HIF-1α-m3604 21 ntTarg: 5′-CUGUAUGGUUUCUUUAUAUGG-3′ (SEQ ID NO: 2070) HIF-1α-m4023 21 ntTarg: 5′-CAUAGUAAACAUCUUGUUUUU-3′ (SEQ ID NO: 2071) HIF-1α-m4064 21 ntTarg: 5′-UUUUCGUUCCCUUGCUCUUUG-3′ (SEQ ID NO: 2072) HIF-1α-m4065 21 ntTarg: 5′-UUUCGUUCCCUUGCUCUUUGU-3′ (SEQ ID NO: 2073) HIF-1α-m4070 21 ntTarg: 5′-UUCCCUUGCUCUUUGUGGUUG-3′ (SEQ ID NO: 2074) HIF-1α-m4549 21 ntTarg: 5′-UUUCCGCGCUCUCAGGGAGCU-3′ (SEQ ID NO: 2075) HIF-1α-m4691 21 ntTarg: 5′-ACCUGAUGUUUCUUUACUUUG-3′ (SEQ ID NO: 2076) HIF-1α-m4692 21 ntTarg: 5′-CCUGAUGUUUCUUUACUUUGC-3′ (SEQ ID NO: 2077) HIF-1α-m4693 21 ntTarg: 5′-CUGAUGUUUCUUUACUUUGCC-3′ (SEQ ID NO: 2078) HIF-1α-m4709 21 ntTarg: 5′-UUGCCAGCUUUAAAAAAGUAU-3′ (SEQ ID NO: 2079) HIF-1α-463 21 ntTarg: 5′-AAAGAUAAGUUCUGAACGUCG-3′ (SEQ ID NO: 3668) HIF-1α-466 21 ntTarg: 5′-GAUAAGUUCUGAACGUCGAAA-3′ (SEQ ID NO: 3669) HIF-1α-468 21 ntTarg: 5′-UAAGUUCUGAACGUCGAAAAG-3′ (SEQ ID NO: 3670) HIF-1α-472 21 ntTarg: 5′-UUCUGAACGUCGAAAAGAAAA-3′ (SEQ ID NO: 3671) HIF-1α-480 21 ntTarg: 5′-GUCGAAAAGAAAAGUCUCGAG-3′ (SEQ ID NO: 3672) HIF-1α-481 21 ntTarg: 5′-UCGAAAAGAAAAGUCUCGAGA-3′ (SEQ ID NO: 3673) HIF-1α-516 21 ntTarg: 5′-GGCGAAGUAAAGAAUCUGAAG-3′ (SEQ ID NO: 3674) HIF-1α-517 21 ntTarg: 5′-GCGAAGUAAAGAAUCUGAAGU-3′ (SEQ ID NO: 3675) HIF-1α-519 21 ntTarg: 5′-GAAGUAAAGAAUCUGAAGUUU-3′ (SEQ ID NO: 3676) HIF-1α-520 21 ntTarg: 5′-AAGUAAAGAAUCUGAAGUUUU-3′ (SEQ ID NO: 3677) HIF-1α-522 21 ntTarg: 5′-GUAAAGAAUCUGAAGUUUUUU-3′ (SEQ ID NO: 3678) HIF-1α-529 21 ntTarg: 5′-AUCUGAAGUUUUUUAUGAGCU-3′ (SEQ ID NO: 3679) HIF-1α-557 21 ntTarg: 5′-CAGUUGCCACUUCCACAUAAU-3′ (SEQ ID NO: 3680) HIF-1α-576 21 ntTarg: 5′-AUGUGAGUUCGCAUCUUGAUA-3′ (SEQ ID NO: 3681) HIF-1α-608 21 ntTarg: 5′-AUGAGGCUUACCAUCAGCUAU-3′ (SEQ ID NO: 3682) HIF-1α-636 21 ntTarg: 5′-UGAGGAAACUUCUGGAUGCUG-3′ (SEQ ID NO: 3683) HIF-1α-652 21 ntTarg: 5′-UGCUGGUGAUUUGGAUAUUGA-3′ (SEQ ID NO: 3684) HIF-1α-654 21 ntTarg: 5′-CUGGUGAUUUGGAUAUUGAAG-3′ (SEQ ID NO: 3685) HIF-1α-660 21 ntTarg: 5′-AUUUGGAUAUUGAAGAUGACA-3′ (SEQ ID NO: 3686) HIF-1α-661 21 ntTarg: 5′-UUUGGAUAUUGAAGAUGACAU-3′ (SEQ ID NO: 3687) HIF-1α-663 21 ntTarg: 5′-UGGAUAUUGAAGAUGACAUGA-3′ (SEQ ID NO: 3688) HIF-1α-664 21 ntTarg: 5′-GGAUAUUGAAGAUGACAUGAA-3′ (SEQ ID NO: 3689) HIF-1α-671 21 ntTarg: 5′-GAAGAUGACAUGAAAGCACAG-3′ (SEQ ID NO: 3690) HIF-1α-672 21 ntTarg: 5′-AAGAUGACAUGAAAGCACAGA-3′ (SEQ ID NO: 3691) HIF-1α-681 21 ntTarg: 5′-UGAAAGCACAGAUGAAUUGCU-3′ (SEQ ID NO: 3692) HIF-1α-687 21 ntTarg: 5′-CACAGAUGAAUUGCUUUUAUU-3′ (SEQ ID NO: 3693) HIF-1α-688 21 ntTarg: 5′-ACAGAUGAAUUGCUUUUAUUU-3′ (SEQ ID NO: 3694) HIF-1α-701 21 ntTarg: 5′-UUUUAUUUGAAAGCCUUGGAU-3′ (SEQ ID NO: 3695) HIF-1α-702 21 ntTarg: 5′-UUUAUUUGAAAGCCUUGGAUG-3′ (SEQ ID NO: 3696) HIF-1α-708 21 ntTarg: 5′-UGAAAGCCUUGGAUGGUUUUG-3′ (SEQ ID NO: 3697) HIF-1α-723 21 ntTarg: 5′-GUUUUGUUAUGGUUCUCACAG-3′ (SEQ ID NO: 3698) HIF-1α-729 21 ntTarg: 5′-UUAUGGUUCUCACAGAUGAUG-3′ (SEQ ID NO: 3699) HIF-1α-730 21 ntTarg: 5′-UAUGGUUCUCACAGAUGAUGG-3′ (SEQ ID NO: 3700) HIF-1α-739 21 ntTarg: 5′-CACAGAUGAUGGUGACAUGAU-3′ (SEQ ID NO: 3701) HIF-1α-744 21 ntTarg: 5′-AUGAUGGUGACAUGAUUUACA-3′ (SEQ ID NO: 3702) HIF-1α-745 21 ntTarg: 5′-UGAUGGUGACAUGAUUUACAU-3′ (SEQ ID NO: 3703) HIF-1α-753 21 ntTarg: 5′-ACAUGAUUUACAUUUCUGAUA-3′ (SEQ ID NO: 3704) HIF-1α-755 21 ntTarg: 5′-AUGAUUUACAUUUCUGAUAAU-3′ (SEQ ID NO: 3705) HIF-1α-757 21 ntTarg: 5′-GAUUUACAUUUCUGAUAAUGU-3′ (SEQ ID NO: 3706) HIF-1α-762 21 ntTarg: 5′-ACAUUUCUGAUAAUGUGAACA-3′ (SEQ ID NO: 3707) HIF-1α-770 21 ntTarg: 5′-GAUAAUGUGAACAAAUACAUG-3′ (SEQ ID NO: 3708) HIF-1α-771 21 ntTarg: 5′-AUAAUGUGAACAAAUACAUGG-3′ (SEQ ID NO: 3709) HIF-1α-772 21 ntTarg: 5′-UAAUGUGAACAAAUACAUGGG-3′ (SEQ ID NO: 3710) HIF-1α-773 21 ntTarg: 5′-AAUGUGAACAAAUACAUGGGA-3′ (SEQ ID NO: 3711) HIF-1α-774 21 ntTarg: 5′-AUGUGAACAAAUACAUGGGAU-3′ (SEQ ID NO: 3712) HIF-1α-775 21 ntTarg: 5′-UGUGAACAAAUACAUGGGAUU-3′ (SEQ ID NO: 3713) HIF-1α-785 21 ntTarg: 5′-UACAUGGGAUUAACUCAGUUU-3′ (SEQ ID NO: 3714) HIF-1α-786 21 ntTarg: 5′-ACAUGGGAUUAACUCAGUUUG-3′ (SEQ ID NO: 3715) HIF-1α-801 21 ntTarg: 5′-AGUUUGAACUAACUGGACACA-3′ (SEQ ID NO: 3716) HIF-1α-811 21 ntTarg: 5′-AACUGGACACAGUGUGUUUGA-3′ (SEQ ID NO: 3717) HIF-1α-812 21 ntTarg: 5′-ACUGGACACAGUGUGUUUGAU-3′ (SEQ ID NO: 3718) HIF-1α-825 21 ntTarg: 5′-UGUUUGAUUUUACUCAUCCAU-3′ (SEQ ID NO: 3719) HIF-1α-827 21 ntTarg: 5′-UUUGAUUUUACUCAUCCAUGU-3′ (SEQ ID NO: 3720) HIF-1α-841 21 ntTarg: 5′-UCCAUGUGACCAUGAGGAAAU-3′ (SEQ ID NO: 3721) HIF-1α-843 21 ntTarg: 5′-CAUGUGACCAUGAGGAAAUGA-3′ (SEQ ID NO: 3722) HIF-1α-849 21 ntTarg: 5′-ACCAUGAGGAAAUGAGAGAAA-3′ (SEQ ID NO: 3723) HIF-1α-861 21 ntTarg: 5′-UGAGAGAAAUGCUUACACACA-3′ (SEQ ID NO: 3724) HIF-1α-865 21 ntTarg: 5′-AGAAAUGCUUACACACAGAAA-3′ (SEQ ID NO: 3725) HIF-1α-866 21 ntTarg: 5′-GAAAUGCUUACACACAGAAAU-3′ (SEQ ID NO: 3726) HIF-1α-880 21 ntTarg: 5′-CAGAAAUGGCCUUGUGAAAAA-3′ (SEQ ID NO: 3727) HIF-1α-881 21 ntTarg: 5′-AGAAAUGGCCUUGUGAAAAAG-3′ (SEQ ID NO: 3728) HIF-1α-882 21 ntTarg: 5′-GAAAUGGCCUUGUGAAAAAGG-3′ (SEQ ID NO: 3729) HIF-1α-883 21 ntTarg: 5′-AAAUGGCCUUGUGAAAAAGGG-3′ (SEQ ID NO: 3730) HIF-1α-888 21 ntTarg: 5′-GCCUUGUGAAAAAGGGUAAAG-3′ (SEQ ID NO: 3731) HIF-1α-904 21 ntTarg: 5′-UAAAGAACAAAACACACAGCG-3′ (SEQ ID NO: 3732) HIF-1α-926 21 ntTarg: 5′-AGCUUUUUUCUCAGAAUGAAG-3′ (SEQ ID NO: 3733) HIF-1α-928 21 ntTarg: 5′-CUUUUUUCUCAGAAUGAAGUG-3′ (SEQ ID NO: 3734) HIF-1α-938 21 ntTarg: 5′-AGAAUGAAGUGUACCCUAACU-3′ (SEQ ID NO: 3735) HIF-1α-962 21 ntTarg: 5′-CGAGGAAGAACUAUGAACAUA-3′ (SEQ ID NO: 3736) HIF-1α-963 21 ntTarg: 5′-GAGGAAGAACUAUGAACAUAA-3′ (SEQ ID NO: 3737) HIF-1α-964 21 ntTarg: 5′-AGGAAGAACUAUGAACAUAAA-3′ (SEQ ID NO: 3738) HIF-1α-1012 21 ntTarg: 5′-CACAGGCCACAUUCACGUAUA-3′ (SEQ ID NO: 3739) HIF-1α-1058 21 ntTarg: 5′-UGUGGGUAUAAGAAACCACCU-3′ (SEQ ID NO: 3740) HIF-1α-1059 21 ntTarg: 5′-GUGGGUAUAAGAAACCACCUA-3′ (SEQ ID NO: 3741) HIF-1α-1123 21 ntTarg: 5′-AAAUAUUGAAAUUCCUUUAGA-3′ (SEQ ID NO: 3742) HIF-1α-1129 21 ntTarg: 5′-UGAAAUUCCUUUAGAUAGCAA-3′ (SEQ ID NO: 3743) HIF-1α-1173 21 ntTarg: 5′-UGGAUAUGAAAUUUUCUUAUU-3′ (SEQ ID NO: 3744) HIF-1α-1176 21 ntTarg: 5′-AUAUGAAAUUUUCUUAUUGUG-3′ (SEQ ID NO: 3745) HIF-1α-1177 21 ntTarg: 5′-UAUGAAAUUUUCUUAUUGUGA-3′ (SEQ ID NO: 3746) HIF-1α-1178 21 ntTarg: 5′-AUGAAAUUUUCUUAUUGUGAU-3′ (SEQ ID NO: 3747) HIF-1α-1180 21 ntTarg: 5′-GAAAUUUUCUUAUUGUGAUGA-3′ (SEQ ID NO: 3748) HIF-1α-1181 21 ntTarg: 5′-AAAUUUUCUUAUUGUGAUGAA-3′ (SEQ ID NO: 3749) HIF-1α-1182 21 ntTarg: 5′-AAUUUUCUUAUUGUGAUGAAA-3′ (SEQ ID NO: 3750) HIF-1α-1186 21 ntTarg: 5′-UUCUUAUUGUGAUGAAAGAAU-3′ (SEQ ID NO: 3751) HIF-1α-1191 21 ntTarg: 5′-AUUGUGAUGAAAGAAUUACCG-3′ (SEQ ID NO: 3752) HIF-1α-1193 21 ntTarg: 5′-UGUGAUGAAAGAAUUACCGAA-3′ (SEQ ID NO: 3753) HIF-1α-1198 21 ntTarg: 5′-UGAAAGAAUUACCGAAUUGAU-3′ (SEQ ID NO: 3754) HIF-1α-1199 21 ntTarg: 5′-GAAAGAAUUACCGAAUUGAUG-3′ (SEQ ID NO: 3755) HIF-1α-1200 21 ntTarg: 5′-AAAGAAUUACCGAAUUGAUGG-3′ (SEQ ID NO: 3756) HIF-1α-1201 21 ntTarg: 5′-AAGAAUUACCGAAUUGAUGGG-3′ (SEQ ID NO: 3757) HIF-1α-1215 21 ntTarg: 5′-UGAUGGGAUAUGAGCCAGAAG-3′ (SEQ ID NO: 3758) HIF-1α-1222 21 ntTarg: 5′-AUAUGAGCCAGAAGAACUUUU-3′ (SEQ ID NO: 3759) HIF-1α-1240 21 ntTarg: 5′-UUUAGGCCGCUCAAUUUAUGA-3′ (SEQ ID NO: 3760) HIF-1α-1254 21 ntTarg: 5′-UUUAUGAAUAUUAUCAUGCUU-3′ (SEQ ID NO: 3761) HIF-1α-1256 21 ntTarg: 5′-UAUGAAUAUUAUCAUGCUUUG-3′ (SEQ ID NO: 3762) HIF-1α-1287 21 ntTarg: 5′-AUCUGACCAAAACUCAUCAUG-3′ (SEQ ID NO: 3763) HIF-1α-1292 21 ntTarg: 5′-ACCAAAACUCAUCAUGAUAUG-3′ (SEQ ID NO: 3764) HIF-1α-1293 21 ntTarg: 5′-CCAAAACUCAUCAUGAUAUGU-3′ (SEQ ID NO: 3765) HIF-1α-1302 21 ntTarg: 5′-AUCAUGAUAUGUUUACUAAAG-3′ (SEQ ID NO: 3766) HIF-1α-1306 21 ntTarg: 5′-UGAUAUGUUUACUAAAGGACA-3′ (SEQ ID NO: 3767) HIF-1α-1362 21 ntTarg: 5′-GAGGUGGAUAUGUCUGGGUUG-3′ (SEQ ID NO: 3768) HIF-1α-1376 21 ntTarg: 5′-UGGGUUGAAACUCAAGCAACU-3′ (SEQ ID NO: 3769) HIF-1α-1393 21 ntTarg: 5′-AACUGUCAUAUAUAACACCAA-3′ (SEQ ID NO: 3770) HIF-1α-1409 21 ntTarg: 5′-ACCAAGAAUUCUCAACCACAG-3′ (SEQ ID NO: 3771) HIF-1α-1425 21 ntTarg: 5′-CACAGUGCAUUGUAUGUGUGA-3′ (SEQ ID NO: 3772) HIF-1α-1426 21 ntTarg: 5′-ACAGUGCAUUGUAUGUGUGAA-3′ (SEQ ID NO: 3773) HIF-1α-1438 21 ntTarg: 5′-AUGUGUGAAUUACGUUGUGAG-3′ (SEQ ID NO: 3774) HIF-1α-1439 21 ntTarg: 5′-UGUGUGAAUUACGUUGUGAGU-3′ (SEQ ID NO: 3775) HIF-1α-1440 21 ntTarg: 5′-GUGUGAAUUACGUUGUGAGUG-3′ (SEQ ID NO: 3776) HIF-1α-1441 21 ntTarg: 5′-UGUGAAUUACGUUGUGAGUGG-3′ (SEQ ID NO: 3777) HIF-1α-1459 21 ntTarg: 5′-UGGUAUUAUUCAGCACGACUU-3′ (SEQ ID NO: 3778) HIF-1α-1477 21 ntTarg: 5′-CUUGAUUUUCUCCCUUCAACA-3′ (SEQ ID NO: 3779) HIF-1α-1494 21 ntTarg: 5′-AACAAACAGAAUGUGUCCUUA-3′ (SEQ ID NO: 3780) HIF-1α-1503 21 ntTarg: 5′-AAUGUGUCCUUAAACCGGUUG-3′ (SEQ ID NO: 3781) HIF-1α-1516 21 ntTarg: 5′-ACCGGUUGAAUCUUCAGAUAU-3′ (SEQ ID NO: 3782) HIF-1α-1517 21 ntTarg: 5′-CCGGUUGAAUCUUCAGAUAUG-3′ (SEQ ID NO: 3783) HIF-1α-1518 21 ntTarg: 5′-CGGUUGAAUCUUCAGAUAUGA-3′ (SEQ ID NO: 3784) HIF-1α-1520 21 ntTarg: 5′-GUUGAAUCUUCAGAUAUGAAA-3′ (SEQ ID NO: 3785) HIF-1α-1521 21 ntTarg: 5′-UUGAAUCUUCAGAUAUGAAAA-3′ (SEQ ID NO: 3786) HIF-1α-1531 21 ntTarg: 5′-AGAUAUGAAAAUGACUCAGCU-3′ (SEQ ID NO: 3787) HIF-1α-1532 21 ntTarg: 5′-GAUAUGAAAAUGACUCAGCUA-3′ (SEQ ID NO: 3788) HIF-1α-1559 21 ntTarg: 5′-AAAGUUGAAUCAGAAGAUACA-3′ (SEQ ID NO: 3789) HIF-1α-1561 21 ntTarg: 5′-AGUUGAAUCAGAAGAUACAAG-3′ (SEQ ID NO: 3790) HIF-1α-1569 21 ntTarg: 5′-CAGAAGAUACAAGUAGCCUCU-3′ (SEQ ID NO: 3791) HIF-1α-1570 21 ntTarg: 5′-AGAAGAUACAAGUAGCCUCUU-3′ (SEQ ID NO: 3792) HIF-1α-1571 21 ntTarg: 5′-GAAGAUACAAGUAGCCUCUUU-3′ (SEQ ID NO: 3793) HIF-1α-1586 21 ntTarg: 5′-CUCUUUGACAAACUUAAGAAG-3′ (SEQ ID NO: 3794) HIF-1α-1587 21 ntTarg: 5′-UCUUUGACAAACUUAAGAAGG-3′ (SEQ ID NO: 3795) HIF-1α-1609 21 ntTarg: 5′-ACCUGAUGCUUUAACUUUGCU-3′ (SEQ ID NO: 3796) HIF-1α-1641 21 ntTarg: 5′-CUGGAGACACAAUCAUAUCUU-3′ (SEQ ID NO: 3797) HIF-1α-1642 21 ntTarg: 5′-UGGAGACACAAUCAUAUCUUU-3′ (SEQ ID NO: 3798) HIF-1α-1701 21 ntTarg: 5′-AACUUGAGGAAGUACCAUUAU-3′ (SEQ ID NO: 3799) HIF-1α-1702 21 ntTarg: 5′-ACUUGAGGAAGUACCAUUAUA-3′ (SEQ ID NO: 3800) HIF-1α-1704 21 ntTarg: 5′-UUGAGGAAGUACCAUUAUAUA-3′ (SEQ ID NO: 3801) HIF-1α-1705 21 ntTarg: 5′-UGAGGAAGUACCAUUAUAUAA-3′ (SEQ ID NO: 3802) HIF-1α-1707 21 ntTarg: 5′-AGGAAGUACCAUUAUAUAAUG-3′ (SEQ ID NO: 3803) HIF-1α-1708 21 ntTarg: 5′-GGAAGUACCAUUAUAUAAUGA-3′ (SEQ ID NO: 3804) HIF-1α-1748 21 ntTarg: 5′-AACGAAAAAUUACAGAAUAUA-3′ (SEQ ID NO: 3805) HIF-1α-1749 21 ntTarg: 5′-ACGAAAAAUUACAGAAUAUAA-3′ (SEQ ID NO: 3806) HIF-1α-1752 21 ntTarg: 5′-AAAAAUUACAGAAUAUAAAUU-3′ (SEQ ID NO: 3807) HIF-1α-1758 21 ntTarg: 5′-UACAGAAUAUAAAUUUGGCAA-3′ (SEQ ID NO: 3808) HIF-1α-1759 21 ntTarg: 5′-ACAGAAUAUAAAUUUGGCAAU-3′ (SEQ ID NO: 3809) HIF-1α-1842 21 ntTarg: 5′-AUCAAGAAGUUGCAUUAAAAU-3′ (SEQ ID NO: 3810) HIF-1α-1843 21 ntTarg: 5′-UCAAGAAGUUGCAUUAAAAUU-3′ (SEQ ID NO: 3811) HIF-1α-1857 21 ntTarg: 5′-UAAAAUUAGAACCAAAUCCAG-3′ (SEQ ID NO: 3812) HIF-1α-1858 21 ntTarg: 5′-AAAAUUAGAACCAAAUCCAGA-3′ (SEQ ID NO: 3813) HIF-1α-1874 21 ntTarg: 5′-CCAGAGUCACUGGAACUUUCU-3′ (SEQ ID NO: 3814) HIF-1α-1875 21 ntTarg: 5′-CAGAGUCACUGGAACUUUCUU-3′ (SEQ ID NO: 3815) HIF-1α-1881 21 ntTarg: 5′-CACUGGAACUUUCUUUUACCA-3′ (SEQ ID NO: 3816) HIF-1α-1966 21 ntTarg: 5′-GCCUAAUAGUCCCAGUGAAUA-3′ (SEQ ID NO: 3817) HIF-1α-1967 21 ntTarg: 5′-CCUAAUAGUCCCAGUGAAUAU-3′ (SEQ ID NO: 3818) HIF-1α-1968 21 ntTarg: 5′-CUAAUAGUCCCAGUGAAUAUU-3′ (SEQ ID NO: 3819) HIF-1α-1969 21 ntTarg: 5′-UAAUAGUCCCAGUGAAUAUUG-3′ (SEQ ID NO: 3820) HIF-1α-1970 21 ntTarg: 5′-AAUAGUCCCAGUGAAUAUUGU-3′ (SEQ ID NO: 3821) HIF-1α-1978 21 ntTarg: 5′-CAGUGAAUAUUGUUUUUAUGU-3′ (SEQ ID NO: 3822) HIF-1α-1979 21 ntTarg: 5′-AGUGAAUAUUGUUUUUAUGUG-3′ (SEQ ID NO: 3823) HIF-1α-1981 21 ntTarg: 5′-UGAAUAUUGUUUUUAUGUGGA-3′ (SEQ ID NO: 3824) HIF-1α-1983 21 ntTarg: 5′-AAUAUUGUUUUUAUGUGGAUA-3′ (SEQ ID NO: 3825) HIF-1α-1984 21 ntTarg: 5′-AUAUUGUUUUUAUGUGGAUAG-3′ (SEQ ID NO: 3826) HIF-1α-1986 21 ntTarg: 5′-AUUGUUUUUAUGUGGAUAGUG-3′ (SEQ ID NO: 3827) HIF-1α-1989 21 ntTarg: 5′-GUUUUUAUGUGGAUAGUGAUA-3′ (SEQ ID NO: 3828) HIF-1α-1996 21 ntTarg: 5′-UGUGGAUAGUGAUAUGGUCAA-3′ (SEQ ID NO: 3829) HIF-1α-1998 21 ntTarg: 5′-UGGAUAGUGAUAUGGUCAAUG-3′ (SEQ ID NO: 3830) HIF-1α-1999 21 ntTarg: 5′-GGAUAGUGAUAUGGUCAAUGA-3′ (SEQ ID NO: 3831) HIF-1α-2000 21 ntTarg: 5′-GAUAGUGAUAUGGUCAAUGAA-3′ (SEQ ID NO: 3832) HIF-1α-2004 21 ntTarg: 5′-GUGAUAUGGUCAAUGAAUUCA-3′ (SEQ ID NO: 3833) HIF-1α-2007 21 ntTarg: 5′-AUAUGGUCAAUGAAUUCAAGU-3′ (SEQ ID NO: 3834) HIF-1α-2008 21 ntTarg: 5′-UAUGGUCAAUGAAUUCAAGUU-3′ (SEQ ID NO: 3835) HIF-1α-2013 21 ntTarg: 5′-UCAAUGAAUUCAAGUUGGAAU-3′ (SEQ ID NO: 3836) HIF-1α-2014 21 ntTarg: 5′-CAAUGAAUUCAAGUUGGAAUU-3′ (SEQ ID NO: 3837) HIF-1α-2016 21 ntTarg: 5′-AUGAAUUCAAGUUGGAAUUGG-3′ (SEQ ID NO: 3838) HIF-1α-2022 21 ntTarg: 5′-UCAAGUUGGAAUUGGUAGAAA-3′ (SEQ ID NO: 3839) HIF-1α-2028 21 ntTarg: 5′-UGGAAUUGGUAGAAAAACUUU-3′ (SEQ ID NO: 3840) HIF-1α-2029 21 ntTarg: 5′-GGAAUUGGUAGAAAAACUUUU-3′ (SEQ ID NO: 3841) HIF-1α-2035 21 ntTarg: 5′-GGUAGAAAAACUUUUUGCUGA-3′ (SEQ ID NO: 3842) HIF-1α-2036 21 ntTarg: 5′-GUAGAAAAACUUUUUGCUGAA-3′ (SEQ ID NO: 3843) HIF-1α-2043 21 ntTarg: 5′-AACUUUUUGCUGAAGACACAG-3′ (SEQ ID NO: 3844) HIF-1α-2050 21 ntTarg: 5′-UGCUGAAGACACAGAAGCAAA-3′ (SEQ ID NO: 3845) HIF-1α-2051 21 ntTarg: 5′-GCUGAAGACACAGAAGCAAAG-3′ (SEQ ID NO: 3846) HIF-1α-2059 21 ntTarg: 5′-CACAGAAGCAAAGAACCCAUU-3′ (SEQ ID NO: 3847) HIF-1α-2068 21 ntTarg: 5′-AAAGAACCCAUUUUCUACUCA-3′ (SEQ ID NO: 3848) HIF-1α-2085 21 ntTarg: 5′-CUCAGGACACAGAUUUAGACU-3′ (SEQ ID NO: 3849) HIF-1α-2092 21 ntTarg: 5′-CACAGAUUUAGACUUGGAGAU-3′ (SEQ ID NO: 3850) HIF-1α-2094 21 ntTarg: 5′-CAGAUUUAGACUUGGAGAUGU-3′ (SEQ ID NO: 3851) HIF-1α-2095 21 ntTarg: 5′-AGAUUUAGACUUGGAGAUGUU-3′ (SEQ ID NO: 3852) HIF-1α-2105 21 ntTarg: 5′-UUGGAGAUGUUAGCUCCCUAU-3′ (SEQ ID NO: 3853) HIF-1α-2134 21 ntTarg: 5′-GGAUGAUGACUUCCAGUUACG-3′ (SEQ ID NO: 3854) HIF-1α-2159 21 ntTarg: 5′-UUCGAUCAGUUGUCACCAUUA-3′ (SEQ ID NO: 3855) HIF-1α-2166 21 ntTarg: 5′-AGUUGUCACCAUUAGAAAGCA-3′ (SEQ ID NO: 3856) HIF-1α-2221 21 ntTarg: 5′-CACAGUUACAGUAUUCCAGCA-3′ (SEQ ID NO: 3857) HIF-1α-2295 21 ntTarg: 5′-AUGAAUUAAAAACAGUGACAA-3′ (SEQ ID NO: 3858) HIF-1α-2296 21 ntTarg: 5′-UGAAUUAAAAACAGUGACAAA-3′ (SEQ ID NO: 3859) HIF-1α-2297 21 ntTarg: 5′-GAAUUAAAAACAGUGACAAAA-3′ (SEQ ID NO: 3860) HIF-1α-2305 21 ntTarg: 5′-AACAGUGACAAAAGACCGUAU-3′ (SEQ ID NO: 3861) HIF-1α-2307 21 ntTarg: 5′-CAGUGACAAAAGACCGUAUGG-3′ (SEQ ID NO: 3862) HIF-1α-2319 21 ntTarg: 5′-ACCGUAUGGAAGACAUUAAAA-3′ (SEQ ID NO: 3863) HIF-1α-2322 21 ntTarg: 5′-GUAUGGAAGACAUUAAAAUAU-3′ (SEQ ID NO: 3864) HIF-1α-2323 21 ntTarg: 5′-UAUGGAAGACAUUAAAAUAUU-3′ (SEQ ID NO: 3865) HIF-1α-2325 21 ntTarg: 5′-UGGAAGACAUUAAAAUAUUGA-3′ (SEQ ID NO: 3866) HIF-1α-2404 21 ntTarg: 5′-AUAUAGAGAUACUCAAAGUCG-3′ (SEQ ID NO: 3867) HIF-1α-2446 21 ntTarg: 5′-AGGAAAAGGAGUCAUAGAACA-3′ (SEQ ID NO: 3868) HIF-1α-2450 21 ntTarg: 5′-AAAGGAGUCAUAGAACAGACA-3′ (SEQ ID NO: 3869) HIF-1α-2451 21 ntTarg: 5′-AAGGAGUCAUAGAACAGACAG-3′ (SEQ ID NO: 3870) HIF-1α-2467 21 ntTarg: 5′-GACAGAAAAAUCUCAUCCAAG-3′ (SEQ ID NO: 3871) HIF-1α-2468 21 ntTarg: 5′-ACAGAAAAAUCUCAUCCAAGA-3′ (SEQ ID NO: 3872) HIF-1α-2495 21 ntTarg: 5′-AACGUGUUAUCUGUCGCUUUG-3′ (SEQ ID NO: 3873) HIF-1α-2496 21 ntTarg: 5′-ACGUGUUAUCUGUCGCUUUGA-3′ (SEQ ID NO: 3874) HIF-1α-2503 21 ntTarg: 5′-AUCUGUCGCUUUGAGUCAAAG-3′ (SEQ ID NO: 3875) HIF-1α-2510 21 ntTarg: 5′-GCUUUGAGUCAAAGAACUACA-3′ (SEQ ID NO: 3876) HIF-1α-2511 21 ntTarg: 5′-CUUUGAGUCAAAGAACUACAG-3′ (SEQ ID NO: 3877) HIF-1α-2517 21 ntTarg: 5′-GUCAAAGAACUACAGUUCCUG-3′ (SEQ ID NO: 3878) HIF-1α-2518 21 ntTarg: 5′-UCAAAGAACUACAGUUCCUGA-3′ (SEQ ID NO: 3879) HIF-1α-2535 21 ntTarg: 5′-CUGAGGAAGAACUAAAUCCAA-3′ (SEQ ID NO: 3880) HIF-1α-2536 21 ntTarg: 5′-UGAGGAAGAACUAAAUCCAAA-3′ (SEQ ID NO: 3881) HIF-1α-2537 21 ntTarg: 5′-GAGGAAGAACUAAAUCCAAAG-3′ (SEQ ID NO: 3882) HIF-1α-2538 21 ntTarg: 5′-AGGAAGAACUAAAUCCAAAGA-3′ (SEQ ID NO: 3883) HIF-1α-2546 21 ntTarg: 5′-CUAAAUCCAAAGAUACUAGCU-3′ (SEQ ID NO: 3884) HIF-1α-2551 21 ntTarg: 5′-UCCAAAGAUACUAGCUUUGCA-3′ (SEQ ID NO: 3885) HIF-1α-2553 21 ntTarg: 5′-CAAAGAUACUAGCUUUGCAGA-3′ (SEQ ID NO: 3886) HIF-1α-2554 21 ntTarg: 5′-AAAGAUACUAGCUUUGCAGAA-3′ (SEQ ID NO: 3887) HIF-1α-2581 21 ntTarg: 5′-GAGAAAGCGAAAAAUGGAACA-3′ (SEQ ID NO: 3888) HIF-1α-2593 21 ntTarg: 5′-AAUGGAACAUGAUGGUUCACU-3′ (SEQ ID NO: 3889) HIF-1α-2599 21 ntTarg: 5′-ACAUGAUGGUUCACUUUUUCA-3′ (SEQ ID NO: 3890) HIF-1α-2611 21 ntTarg: 5′-ACUUUUUCAAGCAGUAGGAAU-3′ (SEQ ID NO: 3891) HIF-1α-2620 21 ntTarg: 5′-AGCAGUAGGAAUUGGAACAUU-3′ (SEQ ID NO: 3892) HIF-1α-2621 21 ntTarg: 5′-GCAGUAGGAAUUGGAACAUUA-3′ (SEQ ID NO: 3893) HIF-1α-2622 21 ntTarg: 5′-CAGUAGGAAUUGGAACAUUAU-3′ (SEQ ID NO: 3894) HIF-1α-2680 21 ntTarg: 5′-UUCUUGGAAACGUGUAAAAGG-3′ (SEQ ID NO: 3895) HIF-1α-2681 21 ntTarg: 5′-UCUUGGAAACGUGUAAAAGGA-3′ (SEQ ID NO: 3896) HIF-1α-2692 21 ntTarg: 5′-UGUAAAAGGAUGCAAAUCUAG-3′ (SEQ ID NO: 3897) HIF-1α-2693 21 ntTarg: 5′-GUAAAAGGAUGCAAAUCUAGU-3′ (SEQ ID NO: 3898) HIF-1α-2698 21 ntTarg: 5′-AGGAUGCAAAUCUAGUGAACA-3′ (SEQ ID NO: 3899) HIF-1α-2702 21 ntTarg: 5′-UGCAAAUCUAGUGAACAGAAU-3′ (SEQ ID NO: 3900) HIF-1α-2708 21 ntTarg: 5′-UCUAGUGAACAGAAUGGAAUG-3′ (SEQ ID NO: 3901) HIF-1α-2709 21 ntTarg: 5′-CUAGUGAACAGAAUGGAAUGG-3′ (SEQ ID NO: 3902) HIF-1α-2716 21 ntTarg: 5′-ACAGAAUGGAAUGGAGCAAAA-3′ (SEQ ID NO: 3903) HIF-1α-2721 21 ntTarg: 5′-AUGGAAUGGAGCAAAAGACAA-3′ (SEQ ID NO: 3904) HIF-1α-2723 21 ntTarg: 5′-GGAAUGGAGCAAAAGACAAUU-3′ (SEQ ID NO: 3905) HIF-1α-2724 21 ntTarg: 5′-GAAUGGAGCAAAAGACAAUUA-3′ (SEQ ID NO: 3906) HIF-1α-2725 21 ntTarg: 5′-AAUGGAGCAAAAGACAAUUAU-3′ (SEQ ID NO: 3907) HIF-1α-2726 21 ntTarg: 5′-AUGGAGCAAAAGACAAUUAUU-3′ (SEQ ID NO: 3908) HIF-1α-2738 21 ntTarg: 5′-ACAAUUAUUUUAAUACCCUCU-3′ (SEQ ID NO: 3909) HIF-1α-2739 21 ntTarg: 5′-CAAUUAUUUUAAUACCCUCUG-3′ (SEQ ID NO: 3910) HIF-1α-2740 21 ntTarg: 5′-AAUUAUUUUAAUACCCUCUGA-3′ (SEQ ID NO: 3911) HIF-1α-2742 21 ntTarg: 5′-UUAUUUUAAUACCCUCUGAUU-3′ (SEQ ID NO: 3912) HIF-1α-2743 21 ntTarg: 5′-UAUUUUAAUACCCUCUGAUUU-3′ (SEQ ID NO: 3913) HIF-1α-2776 21 ntTarg: 5′-GCUGGGGCAAUCAAUGGAUGA-3′ (SEQ ID NO: 3914) HIF-1α-2781 21 ntTarg: 5′-GGCAAUCAAUGGAUGAAAGUG-3′ (SEQ ID NO: 3915) HIF-1α-2817 21 ntTarg: 5′-CCAGUUAUGAUUGUGAAGUUA-3′ (SEQ ID NO: 3916) HIF-1α-2818 21 ntTarg: 5′-CAGUUAUGAUUGUGAAGUUAA-3′ (SEQ ID NO: 3917) HIF-1α-2826 21 ntTarg: 5′-AUUGUGAAGUUAAUGCUCCUA-3′ (SEQ ID NO: 3918) HIF-1α-2830 21 ntTarg: 5′-UGAAGUUAAUGCUCCUAUACA-3′ (SEQ ID NO: 3919) HIF-1α-2869 21 ntTarg: 5′-GCAGGGUGAAGAAUUACUCAG-3′ (SEQ ID NO: 3920) HIF-1α-2875 21 ntTarg: 5′-UGAAGAAUUACUCAGAGCUUU-3′ (SEQ ID NO: 3921) HIF-1α-2877 21 ntTarg: 5′-AAGAAUUACUCAGAGCUUUGG-3′ (SEQ ID NO: 3922) HIF-1α-2885 21 ntTarg: 5′-CUCAGAGCUUUGGAUCAAGUU-3′ (SEQ ID NO: 3923) HIF-1α-2900 21 ntTarg: 5′-CAAGUUAACUGAGCUUUUUCU-3′ (SEQ ID NO: 3924) HIF-1α-2902 21 ntTarg: 5′-AGUUAACUGAGCUUUUUCUUA-3′ (SEQ ID NO: 3925) HIF-1α-2913 21 ntTarg: 5′-CUUUUUCUUAAUUUCAUUCCU-3′ (SEQ ID NO: 3926) HIF-1α-2918 21 ntTarg: 5′-UCUUAAUUUCAUUCCUUUUUU-3′ (SEQ ID NO: 3927) HIF-1α-2920 21 ntTarg: 5′-UUAAUUUCAUUCCUUUUUUUG-3′ (SEQ ID NO: 3928) HIF-1α-2943 21 ntTarg: 5′-CACUGGUGGCUCAUUACCUAA-3′ (SEQ ID NO: 3929) HIF-1α-2952 21 ntTarg: 5′-CUCAUUACCUAAAGCAGUCUA-3′ (SEQ ID NO: 3930) HIF-1α-2953 21 ntTarg: 5′-UCAUUACCUAAAGCAGUCUAU-3′ (SEQ ID NO: 3931) HIF-1α-2958 21 ntTarg: 5′-ACCUAAAGCAGUCUAUUUAUA-3′ (SEQ ID NO: 3932) HIF-1α-2960 21 ntTarg: 5′-CUAAAGCAGUCUAUUUAUAUU-3′ (SEQ ID NO: 3933) HIF-1α-2971 21 ntTarg: 5′-UAUUUAUAUUUUCUACAUCUA-3′ (SEQ ID NO: 3934) HIF-1α-2972 21 ntTarg: 5′-AUUUAUAUUUUCUACAUCUAA-3′ (SEQ ID NO: 3935) HIF-1α-2973 21 ntTarg: 5′-UUUAUAUUUUCUACAUCUAAU-3′ (SEQ ID NO: 3936) HIF-1α-2975 21 ntTarg: 5′-UAUAUUUUCUACAUCUAAUUU-3′ (SEQ ID NO: 3937) HIF-1α-2976 21 ntTarg: 5′-AUAUUUUCUACAUCUAAUUUU-3′ (SEQ ID NO: 3938) HIF-1α-3001 21 ntTarg: 5′-GCCUGGCUACAAUACUGCACA-3′ (SEQ ID NO: 3939) HIF-1α-3022 21 ntTarg: 5′-AACUUGGUUAGUUCAAUUUUG-3′ (SEQ ID NO: 3940) HIF-1α-3029 21 ntTarg: 5′-UUAGUUCAAUUUUGAUCCCCU-3′ (SEQ ID NO: 3941) HIF-1α-3037 21 ntTarg: 5′-AUUUUGAUCCCCUUUCUACUU-3′ (SEQ ID NO: 3942) HIF-1α-3038 21 ntTarg: 5′-UUUUGAUCCCCUUUCUACUUA-3′ (SEQ ID NO: 3943) HIF-1α-3039 21 ntTarg: 5′-UUUGAUCCCCUUUCUACUUAA-3′ (SEQ ID NO: 3944) HIF-1α-3046 21 ntTarg: 5′-CCCUUUCUACUUAAUUUACAU-3′ (SEQ ID NO: 3945) HIF-1α-3056 21 ntTarg: 5′-UUAAUUUACAUUAAUGCUCUU-3′ (SEQ ID NO: 3946) HIF-1α-3057 21 ntTarg: 5′-UAAUUUACAUUAAUGCUCUUU-3′ (SEQ ID NO: 3947) HIF-1α-3063 21 ntTarg: 5′-ACAUUAAUGCUCUUUUUUAGU-3′ (SEQ ID NO: 3948) HIF-1α-3064 21 ntTarg: 5′-CAUUAAUGCUCUUUUUUAGUA-3′ (SEQ ID NO: 3949) HIF-1α-3066 21 ntTarg: 5′-UUAAUGCUCUUUUUUAGUAUG-3′ (SEQ ID NO: 3950) HIF-1α-3074 21 ntTarg: 5′-CUUUUUUAGUAUGUUCUUUAA-3′ (SEQ ID NO: 3951) HIF-1α-3078 21 ntTarg: 5′-UUUAGUAUGUUCUUUAAUGCU-3′ (SEQ ID NO: 3952) HIF-1α-3079 21 ntTarg: 5′-UUAGUAUGUUCUUUAAUGCUG-3′ (SEQ ID NO: 3953) HIF-1α-3080 21 ntTarg: 5′-UAGUAUGUUCUUUAAUGCUGG-3′ (SEQ ID NO: 3954) HIF-1α-3103 21 ntTarg: 5′-CACAGACAGCUCAUUUUCUCA-3′ (SEQ ID NO: 3955) HIF-1α-3112 21 ntTarg: 5′-CUCAUUUUCUCAGUUUUUUGG-3′ (SEQ ID NO: 3956) HIF-1α-3113 21 ntTarg: 5′-UCAUUUUCUCAGUUUUUUGGU-3′ (SEQ ID NO: 3957) HIF-1α-3114 21 ntTarg: 5′-CAUUUUCUCAGUUUUUUGGUA-3′ (SEQ ID NO: 3958) HIF-1α-3124 21 ntTarg: 5′-GUUUUUUGGUAUUUAAACCAU-3′ (SEQ ID NO: 3959) HIF-1α-3128 21 ntTarg: 5′-UUUGGUAUUUAAACCAUUGCA-3′ (SEQ ID NO: 3960) HIF-1α-3129 21 ntTarg: 5′-UUGGUAUUUAAACCAUUGCAU-3′ (SEQ ID NO: 3961) HIF-1α-3134 21 ntTarg: 5′-AUUUAAACCAUUGCAUUGCAG-3′ (SEQ ID NO: 3962) HIF-1α-3146 21 ntTarg: 5′-GCAUUGCAGUAGCAUCAUUUU-3′ (SEQ ID NO: 3963) HIF-1α-3151 21 ntTarg: 5′-GCAGUAGCAUCAUUUUAAAAA-3′ (SEQ ID NO: 3964) HIF-1α-3152 21 ntTarg: 5′-CAGUAGCAUCAUUUUAAAAAA-3′ (SEQ ID NO: 3965) HIF-1α-3159 21 ntTarg: 5′-AUCAUUUUAAAAAAUGCACCU-3′ (SEQ ID NO: 3966) HIF-1α-3160 21 ntTarg: 5′-UCAUUUUAAAAAAUGCACCUU-3′ (SEQ ID NO: 3967) HIF-1α-3161 21 ntTarg: 5′-CAUUUUAAAAAAUGCACCUUU-3′ (SEQ ID NO: 3968) HIF-1α-3162 21 ntTarg: 5′-AUUUUAAAAAAUGCACCUUUU-3′ (SEQ ID NO: 3969) HIF-1α-3163 21 ntTarg: 5′-UUUUAAAAAAUGCACCUUUUU-3′ (SEQ ID NO: 3970) HIF-1α-3164 21 ntTarg: 5′-UUUAAAAAAUGCACCUUUUUA-3′ (SEQ ID NO: 3971) HIF-1α-3166 21 ntTarg: 5′-UAAAAAAUGCACCUUUUUAUU-3′ (SEQ ID NO: 3972) HIF-1α-3168 21 ntTarg: 5′-AAAAAUGCACCUUUUUAUUUA-3′ (SEQ ID NO: 3973) HIF-1α-3176 21 ntTarg: 5′-ACCUUUUUAUUUAUUUAUUUU-3′ (SEQ ID NO: 3974) HIF-1α-3182 21 ntTarg: 5′-UUAUUUAUUUAUUUUUGGCUA-3′ (SEQ ID NO: 3975) HIF-1α-3184 21 ntTarg: 5′-AUUUAUUUAUUUUUGGCUAGG-3′ (SEQ ID NO: 3976) HIF-1α-3185 21 ntTarg: 5′-UUUAUUUAUUUUUGGCUAGGG-3′ (SEQ ID NO: 3977) HIF-1α-3186 21 ntTarg: 5′-UUAUUUAUUUUUGGCUAGGGA-3′ (SEQ ID NO: 3978) HIF-1α-3187 21 ntTarg: 5′-UAUUUAUUUUUGGCUAGGGAG-3′ (SEQ ID NO: 3979) HIF-1α-3202 21 ntTarg: 5′-AGGGAGUUUAUCCCUUUUUCG-3′ (SEQ ID NO: 3980) HIF-1α-3203 21 ntTarg: 5′-GGGAGUUUAUCCCUUUUUCGA-3′ (SEQ ID NO: 3981) HIF-1α-3204 21 ntTarg: 5′-GGAGUUUAUCCCUUUUUCGAA-3′ (SEQ ID NO: 3982) HIF-1α-3205 21 ntTarg: 5′-GAGUUUAUCCCUUUUUCGAAU-3′ (SEQ ID NO: 3983) HIF-1α-3206 21 ntTarg: 5′-AGUUUAUCCCUUUUUCGAAUU-3′ (SEQ ID NO: 3984) HIF-1α-3207 21 ntTarg: 5′-GUUUAUCCCUUUUUCGAAUUA-3′ (SEQ ID NO: 3985) HIF-1α-3219 21 ntTarg: 5′-UUCGAAUUAUUUUUAAGAAGA-3′ (SEQ ID NO: 3986) HIF-1α-3224 21 ntTarg: 5′-AUUAUUUUUAAGAAGAUGCCA-3′ (SEQ ID NO: 3987) HIF-1α-3225 21 ntTarg: 5′-UUAUUUUUAAGAAGAUGCCAA-3′ (SEQ ID NO: 3988) HIF-1α-3227 21 ntTarg: 5′-AUUUUUAAGAAGAUGCCAAUA-3′ (SEQ ID NO: 3989) HIF-1α-3228 21 ntTarg: 5′-UUUUUAAGAAGAUGCCAAUAU-3′ (SEQ ID NO: 3990) HIF-1α-3230 21 ntTarg: 5′-UUUAAGAAGAUGCCAAUAUAA-3′ (SEQ ID NO: 3991) HIF-1α-3231 21 ntTarg: 5′-UUAAGAAGAUGCCAAUAUAAU-3′ (SEQ ID NO: 3992) HIF-1α-3233 21 ntTarg: 5′-AAGAAGAUGCCAAUAUAAUUU-3′ (SEQ ID NO: 3993) HIF-1α-3234 21 ntTarg: 5′-AGAAGAUGCCAAUAUAAUUUU-3′ (SEQ ID NO: 3994) HIF-1α-3235 21 ntTarg: 5′-GAAGAUGCCAAUAUAAUUUUU-3′ (SEQ ID NO: 3995) HIF-1α-3242 21 ntTarg: 5′-CCAAUAUAAUUUUUGUAAGAA-3′ (SEQ ID NO: 3996) HIF-1α-3246 21 ntTarg: 5′-UAUAAUUUUUGUAAGAAGGCA-3′ (SEQ ID NO: 3997) HIF-1α-3248 21 ntTarg: 5′-UAAUUUUUGUAAGAAGGCAGU-3′ (SEQ ID NO: 3998) HIF-1α-3277 21 ntTarg: 5′-AUCAUGAUCAUAGGCAGUUGA-3′ (SEQ ID NO: 3999) HIF-1α-3279 21 ntTarg: 5′-CAUGAUCAUAGGCAGUUGAAA-3′ (SEQ ID NO: 4000) HIF-1α-3283 21 ntTarg: 5′-AUCAUAGGCAGUUGAAAAAUU-3′ (SEQ ID NO: 4001) HIF-1α-3285 21 ntTarg: 5′-CAUAGGCAGUUGAAAAAUUUU-3′ (SEQ ID NO: 4002) HIF-1α-3293 21 ntTarg: 5′-GUUGAAAAAUUUUUACACCUU-3′ (SEQ ID NO: 4003) HIF-1α-3294 21 ntTarg: 5′-UUGAAAAAUUUUUACACCUUU-3′ (SEQ ID NO: 4004) HIF-1α-3295 21 ntTarg: 5′-UGAAAAAUUUUUACACCUUUU-3′ (SEQ ID NO: 4005) HIF-1α-3296 21 ntTarg: 5′-GAAAAAUUUUUACACCUUUUU-3′ (SEQ ID NO: 4006) HIF-1α-3297 21 ntTarg: 5′-AAAAAUUUUUACACCUUUUUU-3′ (SEQ ID NO: 4007) HIF-1α-3311 21 ntTarg: 5′-CUUUUUUUUCACAUUUUACAU-3′ (SEQ ID NO: 4008) HIF-1α-3312 21 ntTarg: 5′-UUUUUUUUCACAUUUUACAUA-3′ (SEQ ID NO: 4009) HIF-1α-3313 21 ntTarg: 5′-UUUUUUUCACAUUUUACAUAA-3′ (SEQ ID NO: 4010) HIF-1α-3314 21 ntTarg: 5′-UUUUUUCACAUUUUACAUAAA-3′ (SEQ ID NO: 4011) HIF-1α-3320 21 ntTarg: 5′-CACAUUUUACAUAAAUAAUAA-3′ (SEQ ID NO: 4012) HIF-1α-3359 21 ntTarg: 5′-UGGUAGCCACAAUUGCACAAU-3′ (SEQ ID NO: 4013) HIF-1α-3375 21 ntTarg: 5′-ACAAUAUAUUUUCUUAAAAAA-3′ (SEQ ID NO: 4014) HIF-1α-3385 21 ntTarg: 5′-UUCUUAAAAAAUACCAGCAGU-3′ (SEQ ID NO: 4015) HIF-1α-3400 21 ntTarg: 5′-AGCAGUUACUCAUGGAAUAUA-3′ (SEQ ID NO: 4016) HIF-1α-3408 21 ntTarg: 5′-CUCAUGGAAUAUAUUCUGCGU-3′ (SEQ ID NO: 4017) HIF-1α-3409 21 ntTarg: 5′-UCAUGGAAUAUAUUCUGCGUU-3′ (SEQ ID NO: 4018) HIF-1α-3410 21 ntTarg: 5′-CAUGGAAUAUAUUCUGCGUUU-3′ (SEQ ID NO: 4019) HIF-1α-3411 21 ntTarg: 5′-AUGGAAUAUAUUCUGCGUUUA-3′ (SEQ ID NO: 4020) HIF-1α-3412 21 ntTarg: 5′-UGGAAUAUAUUCUGCGUUUAU-3′ (SEQ ID NO: 4021) HIF-1α-3413 21 ntTarg: 5′-GGAAUAUAUUCUGCGUUUAUA-3′ (SEQ ID NO: 4022) HIF-1α-3414 21 ntTarg: 5′-GAAUAUAUUCUGCGUUUAUAA-3′ (SEQ ID NO: 4023) HIF-1α-3429 21 ntTarg: 5′-UUAUAAAACUAGUUUUUAAGA-3′ (SEQ ID NO: 4024) HIF-1α-3435 21 ntTarg: 5′-AACUAGUUUUUAAGAAGAAAU-3′ (SEQ ID NO: 4025) HIF-1α-3436 21 ntTarg: 5′-ACUAGUUUUUAAGAAGAAAUU-3′ (SEQ ID NO: 4026) HIF-1α-3437 21 ntTarg: 5′-CUAGUUUUUAAGAAGAAAUUU-3′ (SEQ ID NO: 4027) HIF-1α-3438 21 ntTarg: 5′-UAGUUUUUAAGAAGAAAUUUU-3′ (SEQ ID NO: 4028) HIF-1α-3441 21 ntTarg: 5′-UUUUUAAGAAGAAAUUUUUUU-3′ (SEQ ID NO: 4029) HIF-1α-3447 21 ntTarg: 5′-AGAAGAAAUUUUUUUUGGCCU-3′ (SEQ ID NO: 4030) HIF-1α-3449 21 ntTarg: 5′-AAGAAAUUUUUUUUGGCCUAU-3′ (SEQ ID NO: 4031) HIF-1α-3451 21 ntTarg: 5′-GAAAUUUUUUUUGGCCUAUGA-3′ (SEQ ID NO: 4032) HIF-1α-3453 21 ntTarg: 5′-AAUUUUUUUUGGCCUAUGAAA-3′ (SEQ ID NO: 4033) HIF-1α-3456 21 ntTarg: 5′-UUUUUUUGGCCUAUGAAAUUG-3′ (SEQ ID NO: 4034) HIF-1α-3457 21 ntTarg: 5′-UUUUUUGGCCUAUGAAAUUGU-3′ (SEQ ID NO: 4035) HIF-1α-3458 21 ntTarg: 5′-UUUUUGGCCUAUGAAAUUGUU-3′ (SEQ ID NO: 4036) HIF-1α-3459 21 ntTarg: 5′-UUUUGGCCUAUGAAAUUGUUA-3′ (SEQ ID NO: 4037) HIF-1α-3464 21 ntTarg: 5′-GCCUAUGAAAUUGUUAAACCU-3′ (SEQ ID NO: 4038) HIF-1α-3466 21 ntTarg: 5′-CUAUGAAAUUGUUAAACCUGG-3′ (SEQ ID NO: 4039) HIF-1α-3470 21 ntTarg: 5′-GAAAUUGUUAAACCUGGAACA-3′ (SEQ ID NO: 4040) HIF-1α-3471 21 ntTarg: 5′-AAAUUGUUAAACCUGGAACAU-3′ (SEQ ID NO: 4041) HIF-1α-3481 21 ntTarg: 5′-ACCUGGAACAUGACAUUGUUA-3′ (SEQ ID NO: 4042) HIF-1α-3487 21 ntTarg: 5′-AACAUGACAUUGUUAAUCAUA-3′ (SEQ ID NO: 4043) HIF-1α-3488 21 ntTarg: 5′-ACAUGACAUUGUUAAUCAUAU-3′ (SEQ ID NO: 4044) HIF-1α-3492 21 ntTarg: 5′-GACAUUGUUAAUCAUAUAAUA-3′ (SEQ ID NO: 4045) HIF-1α-3494 21 ntTarg: 5′-CAUUGUUAAUCAUAUAAUAAU-3′ (SEQ ID NO: 4046) HIF-1α-3495 21 ntTarg: 5′-AUUGUUAAUCAUAUAAUAAUG-3′ (SEQ ID NO: 4047) HIF-1α-3496 21 ntTarg: 5′-UUGUUAAUCAUAUAAUAAUGA-3′ (SEQ ID NO: 4048) HIF-1α-3503 21 ntTarg: 5′-UCAUAUAAUAAUGAUUCUUAA-3′ (SEQ ID NO: 4049) HIF-1α-3504 21 ntTarg: 5′-CAUAUAAUAAUGAUUCUUAAA-3′ (SEQ ID NO: 4050) HIF-1α-3508 21 ntTarg: 5′-UAAUAAUGAUUCUUAAAUGCU-3′ (SEQ ID NO: 4051) HIF-1α-3511 21 ntTarg: 5′-UAAUGAUUCUUAAAUGCUGUA-3′ (SEQ ID NO: 4052) HIF-1α-3512 21 ntTarg: 5′-AAUGAUUCUUAAAUGCUGUAU-3′ (SEQ ID NO: 4053) HIF-1α-3513 21 ntTarg: 5′-AUGAUUCUUAAAUGCUGUAUG-3′ (SEQ ID NO: 4054) HIF-1α-3518 21 ntTarg: 5′-UCUUAAAUGCUGUAUGGUUUA-3′ (SEQ ID NO: 4055) HIF-1α-3519 21 ntTarg: 5′-CUUAAAUGCUGUAUGGUUUAU-3′ (SEQ ID NO: 4056) HIF-1α-3521 21 ntTarg: 5′-UAAAUGCUGUAUGGUUUAUUA-3′ (SEQ ID NO: 4057) HIF-1α-3528 21 ntTarg: 5′-UGUAUGGUUUAUUAUUUAAAU-3′ (SEQ ID NO: 4058) HIF-1α-3530 21 ntTarg: 5′-UAUGGUUUAUUAUUUAAAUGG-3′ (SEQ ID NO: 4059) HIF-1α-3531 21 ntTarg: 5′-AUGGUUUAUUAUUUAAAUGGG-3′ (SEQ ID NO: 4060) HIF-1α-3533 21 ntTarg: 5′-GGUUUAUUAUUUAAAUGGGUA-3′ (SEQ ID NO: 4061) HIF-1α-3534 21 ntTarg: 5′-GUUUAUUAUUUAAAUGGGUAA-3′ (SEQ ID NO: 4062) HIF-1α-3539 21 ntTarg: 5′-UUAUUUAAAUGGGUAAAGCCA-3′ (SEQ ID NO: 4063) HIF-1α-3545 21 ntTarg: 5′-AAAUGGGUAAAGCCAUUUACA-3′ (SEQ ID NO: 4064) HIF-1α-3548 21 ntTarg: 5′-UGGGUAAAGCCAUUUACAUAA-3′ (SEQ ID NO: 4065) HIF-1α-3550 21 ntTarg: 5′-GGUAAAGCCAUUUACAUAAUA-3′ (SEQ ID NO: 4066) HIF-1α-3551 21 ntTarg: 5′-GUAAAGCCAUUUACAUAAUAU-3′ (SEQ ID NO: 4067) HIF-1α-3556 21 ntTarg: 5′-GCCAUUUACAUAAUAUAGAAA-3′ (SEQ ID NO: 4068) HIF-1α-3565 21 ntTarg: 5′-AUAAUAUAGAAAGAUAUGCAU-3′ (SEQ ID NO: 4069) HIF-1α-3566 21 ntTarg: 5′-UAAUAUAGAAAGAUAUGCAUA-3′ (SEQ ID NO: 4070) HIF-1α-3567 21 ntTarg: 5′-AAUAUAGAAAGAUAUGCAUAU-3′ (SEQ ID NO: 4071) HIF-1α-3571 21 ntTarg: 5′-UAGAAAGAUAUGCAUAUAUCU-3′ (SEQ ID NO: 4072) HIF-1α-3574 21 ntTarg: 5′-AAAGAUAUGCAUAUAUCUAGA-3′ (SEQ ID NO: 4073) HIF-1α-3575 21 ntTarg: 5′-AAGAUAUGCAUAUAUCUAGAA-3′ (SEQ ID NO: 4074) HIF-1α-3576 21 ntTarg: 5′-AGAUAUGCAUAUAUCUAGAAG-3′ (SEQ ID NO: 4075) HIF-1α-3581 21 ntTarg: 5′-UGCAUAUAUCUAGAAGGUAUG-3′ (SEQ ID NO: 4076) HIF-1α-3582 21 ntTarg: 5′-GCAUAUAUCUAGAAGGUAUGU-3′ (SEQ ID NO: 4077) HIF-1α-3589 21 ntTarg: 5′-UCUAGAAGGUAUGUGGCAUUU-3′ (SEQ ID NO: 4078) HIF-1α-3593 21 ntTarg: 5′-GAAGGUAUGUGGCAUUUAUUU-3′ (SEQ ID NO: 4079) HIF-1α-3597 21 ntTarg: 5′-GUAUGUGGCAUUUAUUUGGAU-3′ (SEQ ID NO: 4080) HIF-1α-3599 21 ntTarg: 5′-AUGUGGCAUUUAUUUGGAUAA-3′ (SEQ ID NO: 4081) HIF-1α-3607 21 ntTarg: 5′-UUUAUUUGGAUAAAAUUCUCA-3′ (SEQ ID NO: 4082) HIF-1α-3613 21 ntTarg: 5′-UGGAUAAAAUUCUCAAUUCAG-3′ (SEQ ID NO: 4083) HIF-1α-3615 21 ntTarg: 5′-GAUAAAAUUCUCAAUUCAGAG-3′ (SEQ ID NO: 4084) HIF-1α-3617 21 ntTarg: 5′-UAAAAUUCUCAAUUCAGAGAA-3′ (SEQ ID NO: 4085) HIF-1α-3625 21 ntTarg: 5′-UCAAUUCAGAGAAAUCAUCUG-3′ (SEQ ID NO: 4086) HIF-1α-3629 21 ntTarg: 5′-UUCAGAGAAAUCAUCUGAUGU-3′ (SEQ ID NO: 4087) HIF-1α-3634 21 ntTarg: 5′-AGAAAUCAUCUGAUGUUUCUA-3′ (SEQ ID NO: 4088) HIF-1α-3642 21 ntTarg: 5′-UCUGAUGUUUCUAUAGUCACU-3′ (SEQ ID NO: 4089) HIF-1α-3643 21 ntTarg: 5′-CUGAUGUUUCUAUAGUCACUU-3′ (SEQ ID NO: 4090) HIF-1α-3671 21 ntTarg: 5′-UCAAAAGAAAACAAUACCCUA-3′ (SEQ ID NO: 4091) HIF-1α-3673 21 ntTarg: 5′-AAAAGAAAACAAUACCCUAUG-3′ (SEQ ID NO: 4092) HIF-1α-3674 21 ntTarg: 5′-AAAGAAAACAAUACCCUAUGU-3′ (SEQ ID NO: 4093) HIF-1α-3676 21 ntTarg: 5′-AGAAAACAAUACCCUAUGUAG-3′ (SEQ ID NO: 4094) HIF-1α-3680 21 ntTarg: 5′-AACAAUACCCUAUGUAGUUGU-3′ (SEQ ID NO: 4095) HIF-1α-3688 21 ntTarg: 5′-CCUAUGUAGUUGUGGAAGUUU-3′ (SEQ ID NO: 4096) HIF-1α-3689 21 ntTarg: 5′-CUAUGUAGUUGUGGAAGUUUA-3′ (SEQ ID NO: 4097) HIF-1α-3694 21 ntTarg: 5′-UAGUUGUGGAAGUUUAUGCUA-3′ (SEQ ID NO: 4098) HIF-1α-3695 21 ntTarg: 5′-AGUUGUGGAAGUUUAUGCUAA-3′ (SEQ ID NO: 4099) HIF-1α-3697 21 ntTarg: 5′-UUGUGGAAGUUUAUGCUAAUA-3′ (SEQ ID NO: 4100) HIF-1α-3699 21 ntTarg: 5′-GUGGAAGUUUAUGCUAAUAUU-3′ (SEQ ID NO: 4101) HIF-1α-3700 21 ntTarg: 5′-UGGAAGUUUAUGCUAAUAUUG-3′ (SEQ ID NO: 4102) HIF-1α-3701 21 ntTarg: 5′-GGAAGUUUAUGCUAAUAUUGU-3′ (SEQ ID NO: 4103) HIF-1α-3703 21 ntTarg: 5′-AAGUUUAUGCUAAUAUUGUGU-3′ (SEQ ID NO: 4104) HIF-1α-3710 21 ntTarg: 5′-UGCUAAUAUUGUGUAACUGAU-3′ (SEQ ID NO: 4105) HIF-1α-3712 21 ntTarg: 5′-CUAAUAUUGUGUAACUGAUAU-3′ (SEQ ID NO: 4106) HIF-1α-3714 21 ntTarg: 5′-AAUAUUGUGUAACUGAUAUUA-3′ (SEQ ID NO: 4107) HIF-1α-3724 21 ntTarg: 5′-AACUGAUAUUAAACCUAAAUG-3′ (SEQ ID NO: 4108) HIF-1α-3756 21 ntTarg: 5′-CUGUUGGUAUAAAGAUAUUUU-3′ (SEQ ID NO: 4109) HIF-1α-3761 21 ntTarg: 5′-GGUAUAAAGAUAUUUUGAGCA-3′ (SEQ ID NO: 4110) HIF-1α-3765 21 ntTarg: 5′-UAAAGAUAUUUUGAGCAGACU-3′ (SEQ ID NO: 4111) HIF-1α-3766 21 ntTarg: 5′-AAAGAUAUUUUGAGCAGACUG-3′ (SEQ ID NO: 4112) HIF-1α-3767 21 ntTarg: 5′-AAGAUAUUUUGAGCAGACUGU-3′ (SEQ ID NO: 4113) HIF-1α-3772 21 ntTarg: 5′-AUUUUGAGCAGACUGUAAACA-3′ (SEQ ID NO: 4114) HIF-1α-3774 21 ntTarg: 5′-UUUGAGCAGACUGUAAACAAG-3′ (SEQ ID NO: 4115) HIF-1α-3778 21 ntTarg: 5′-AGCAGACUGUAAACAAGAAAA-3′ (SEQ ID NO: 4116) HIF-1α-3782 21 ntTarg: 5′-GACUGUAAACAAGAAAAAAAA-3′ (SEQ ID NO: 4117) HIF-1α-3783 21 ntTarg: 5′-ACUGUAAACAAGAAAAAAAAA-3′ (SEQ ID NO: 4118) HIF-1α-3795 21 ntTarg: 5′-AAAAAAAAAAUCAUGCAUUCU-3′ (SEQ ID NO: 4119) HIF-1α-3796 21 ntTarg: 5′-AAAAAAAAAUCAUGCAUUCUU-3′ (SEQ ID NO: 4120) HIF-1α-3804 21 ntTarg: 5′-AUCAUGCAUUCUUAGCAAAAU-3′ (SEQ ID NO: 4121) HIF-1α-3812 21 ntTarg: 5′-UUCUUAGCAAAAUUGCCUAGU-3′ (SEQ ID NO: 4122) HIF-1α-3813 21 ntTarg: 5′-UCUUAGCAAAAUUGCCUAGUA-3′ (SEQ ID NO: 4123) HIF-1α-3818 21 ntTarg: 5′-GCAAAAUUGCCUAGUAUGUUA-3′ (SEQ ID NO: 4124) HIF-1α-3820 21 ntTarg: 5′-AAAAUUGCCUAGUAUGUUAAU-3′ (SEQ ID NO: 4125) HIF-1α-3821 21 ntTarg: 5′-AAAUUGCCUAGUAUGUUAAUU-3′ (SEQ ID NO: 4126) HIF-1α-3827 21 ntTarg: 5′-CCUAGUAUGUUAAUUUGCUCA-3′ (SEQ ID NO: 4127) HIF-1α-3828 21 ntTarg: 5′-CUAGUAUGUUAAUUUGCUCAA-3′ (SEQ ID NO: 4128) HIF-1α-3829 21 ntTarg: 5′-UAGUAUGUUAAUUUGCUCAAA-3′ (SEQ ID NO: 4129) HIF-1α-3835 21 ntTarg: 5′-GUUAAUUUGCUCAAAAUACAA-3′ (SEQ ID NO: 4130) HIF-1α-3836 21 ntTarg: 5′-UUAAUUUGCUCAAAAUACAAU-3′ (SEQ ID NO: 4131) HIF-1α-3838 21 ntTarg: 5′-AAUUUGCUCAAAAUACAAUGU-3′ (SEQ ID NO: 4132) HIF-1α-3844 21 ntTarg: 5′-CUCAAAAUACAAUGUUUGAUU-3′ (SEQ ID NO: 4133) HIF-1α-3846 21 ntTarg: 5′-CAAAAUACAAUGUUUGAUUUU-3′ (SEQ ID NO: 4134) HIF-1α-3847 21 ntTarg: 5′-AAAAUACAAUGUUUGAUUUUA-3′ (SEQ ID NO: 4135) HIF-1α-3853 21 ntTarg: 5′-CAAUGUUUGAUUUUAUGCACU-3′ (SEQ ID NO: 4136) HIF-1α-3854 21 ntTarg: 5′-AAUGUUUGAUUUUAUGCACUU-3′ (SEQ ID NO: 4137) HIF-1α-3864 21 ntTarg: 5′-UUUAUGCACUUUGUCGCUAUU-3′ (SEQ ID NO: 4138) HIF-1α-3872 21 ntTarg: 5′-CUUUGUCGCUAUUAACAUCCU-3′ (SEQ ID NO: 4139) HIF-1α-3891 21 ntTarg: 5′-CUUUUUUUCAUGUAGAUUUCA-3′ (SEQ ID NO: 4140) HIF-1α-3892 21 ntTarg: 5′-UUUUUUUCAUGUAGAUUUCAA-3′ (SEQ ID NO: 4141) HIF-1α-3897 21 ntTarg: 5′-UUCAUGUAGAUUUCAAUAAUU-3′ (SEQ ID NO: 4142) HIF-1α-3898 21 ntTarg: 5′-UCAUGUAGAUUUCAAUAAUUG-3′ (SEQ ID NO: 4143) HIF-1α-3899 21 ntTarg: 5′-CAUGUAGAUUUCAAUAAUUGA-3′ (SEQ ID NO: 4144) HIF-1α-3900 21 ntTarg: 5′-AUGUAGAUUUCAAUAAUUGAG-3′ (SEQ ID NO: 4145) HIF-1α-3901 21 ntTarg: 5′-UGUAGAUUUCAAUAAUUGAGU-3′ (SEQ ID NO: 4146) HIF-1α-3902 21 ntTarg: 5′-GUAGAUUUCAAUAAUUGAGUA-3′ (SEQ ID NO: 4147) HIF-1α-3903 21 ntTarg: 5′-UAGAUUUCAAUAAUUGAGUAA-3′ (SEQ ID NO: 4148) HIF-1α-3904 21 ntTarg: 5′-AGAUUUCAAUAAUUGAGUAAU-3′ (SEQ ID NO: 4149) HIF-1α-3910 21 ntTarg: 5′-CAAUAAUUGAGUAAUUUUAGA-3′ (SEQ ID NO: 4150) HIF-1α-3914 21 ntTarg: 5′-AAUUGAGUAAUUUUAGAAGCA-3′ (SEQ ID NO: 4151) HIF-1α-3915 21 ntTarg: 5′-AUUGAGUAAUUUUAGAAGCAU-3′ (SEQ ID NO: 4152) HIF-1α-3917 21 ntTarg: 5′-UGAGUAAUUUUAGAAGCAUUA-3′ (SEQ ID NO: 4153) HIF-1α-3921 21 ntTarg: 5′-UAAUUUUAGAAGCAUUAUUUU-3′ (SEQ ID NO: 4154) HIF-1α-3925 21 ntTarg: 5′-UUUAGAAGCAUUAUUUUAGGA-3′ (SEQ ID NO: 4155) HIF-1α-3927 21 ntTarg: 5′-UAGAAGCAUUAUUUUAGGAAU-3′ (SEQ ID NO: 4156) HIF-1α-3931 21 ntTarg: 5′-AGCAUUAUUUUAGGAAUAUAU-3′ (SEQ ID NO: 4157) HIF-1α-3933 21 ntTarg: 5′-CAUUAUUUUAGGAAUAUAUAG-3′ (SEQ ID NO: 4158) HIF-1α-3941 21 ntTarg: 5′-UAGGAAUAUAUAGUUGUCACA-3′ (SEQ ID NO: 4159) HIF-1α-3942 21 ntTarg: 5′-AGGAAUAUAUAGUUGUCACAG-3′ (SEQ ID NO: 4160) HIF-1α-3943 21 ntTarg: 5′-GGAAUAUAUAGUUGUCACAGU-3′ (SEQ ID NO: 4161) HIF-1α-3945 21 ntTarg: 5′-AAUAUAUAGUUGUCACAGUAA-3′ (SEQ ID NO: 4162) HIF-1α-3946 21 ntTarg: 5′-AUAUAUAGUUGUCACAGUAAA-3′ (SEQ ID NO: 4163) HIF-1α-3951 21 ntTarg: 5′-UAGUUGUCACAGUAAAUAUCU-3′ (SEQ ID NO: 4164) HIF-1α-3952 21 ntTarg: 5′-AGUUGUCACAGUAAAUAUCUU-3′ (SEQ ID NO: 4165) HIF-1α-3962 21 ntTarg: 5′-GUAAAUAUCUUGUUUUUUCUA-3′ (SEQ ID NO: 4166) HIF-1α-3963 21 ntTarg: 5′-UAAAUAUCUUGUUUUUUCUAU-3′ (SEQ ID NO: 4167) HIF-1α-3968 21 ntTarg: 5′-AUCUUGUUUUUUCUAUGUACA-3′ (SEQ ID NO: 4168) HIF-1α-3969 21 ntTarg: 5′-UCUUGUUUUUUCUAUGUACAU-3′ (SEQ ID NO: 4169) HIF-1α-3970 21 ntTarg: 5′-CUUGUUUUUUCUAUGUACAUU-3′ (SEQ ID NO: 4170) HIF-1α-3971 21 ntTarg: 5′-UUGUUUUUUCUAUGUACAUUG-3′ (SEQ ID NO: 4171) HIF-1α-3978 21 ntTarg: 5′-UUCUAUGUACAUUGUACAAAU-3′ (SEQ ID NO: 4172) HIF-1α-3979 21 ntTarg: 5′-UCUAUGUACAUUGUACAAAUU-3′ (SEQ ID NO: 4173) HIF-1α-3997 21 ntTarg: 5′-AUUUUUCAUUCCUUUUGCUCU-3′ (SEQ ID NO: 4174) HIF-1α-4021 21 ntTarg: 5′-UGGUUGGAUCUAACACUAACU-3′ (SEQ ID NO: 4175) HIF-1α-4022 21 ntTarg: 5′-GGUUGGAUCUAACACUAACUG-3′ (SEQ ID NO: 4176) HIF-1α-4024 21 ntTarg: 5′-UUGGAUCUAACACUAACUGUA-3′ (SEQ ID NO: 4177) HIF-1α-4040 21 ntTarg: 5′-CUGUAUUGUUUUGUUACAUCA-3′ (SEQ ID NO: 4178) HIF-1α-4041 21 ntTarg: 5′-UGUAUUGUUUUGUUACAUCAA-3′ (SEQ ID NO: 4179) HIF-1α-4042 21 ntTarg: 5′-GUAUUGUUUUGUUACAUCAAA-3′ (SEQ ID NO: 4180) HIF-1α-4044 21 ntTarg: 5′-AUUGUUUUGUUACAUCAAAUA-3′ (SEQ ID NO: 4181) HIF-1α-4072 21 ntTarg: 5′-UCUGUGGACCAGGCAAAAAAA-3′ (SEQ ID NO: 4182) HIF-1α-4073 21 ntTarg: 5′-CUGUGGACCAGGCAAAAAAAA-3′ (SEQ ID NO: 4183) HIF-1α-4079 21 ntTarg: 5′-ACCAGGCAAAAAAAAAAAAAA-3′ (SEQ ID NO: 4184) HIF-1α-2610t2 21 ntTarg: 5′-CACUUUUUCAAGCAGUAGGAA-3′ (SEQ ID NO: 4185) HIF-1α-2611t2 21 ntTarg: 5′-ACUUUUUCAAGCAGUAGGAAU-3′ (SEQ ID NO: 4186) HIF-1α-2616t2 21 ntTarg: 5′-UUCAAGCAGUAGGAAUUAUUU-3′ (SEQ ID NO: 4187) HIF-1α-2620t2 21 ntTarg: 5′-AGCAGUAGGAAUUAUUUAGCA-3′ (SEQ ID NO: 4188) HIF-1α-2622t2 21 ntTarg: 5′-CAGUAGGAAUUAUUUAGCAUG-3′ (SEQ ID NO: 4189) HIF-1α-2623t2 21 ntTarg: 5′-AGUAGGAAUUAUUUAGCAUGU-3′ (SEQ ID NO: 4190) HIF-1α-2624t2 21 ntTarg: 5′-GUAGGAAUUAUUUAGCAUGUA-3′ (SEQ ID NO: 4191) 21mer Targets ascDNAs HIF-1α-81 21 nt Targ: 5′-CCGCGCGCCCGAGCGCGCCTC-3′ (SEQ ID NO:4192) HIF-1α-83 21 nt Targ: 5′-GCGCGCCCGAGCGCGCCTCCG-3′ (SEQ ID NO:4193) HIF-1α-85 21 nt Targ: 5′-GCGCCCGAGCGCGCCTCCGCC-3′ (SEQ ID NO:4194) HIF-1α-87 21 nt Targ: 5′-GCCCGAGCGCGCCTCCGCCCT-3′ (SEQ ID NO:4195) HIF-1α-89 21 nt Targ: 5′-CCGAGCGCGCCTCCGCCCTTG-3′ (SEQ ID NO:4196) HIF-1α-123 21 nt Targ: 5′-GCTGCCTCAGCTCCTCAGTGC-3′ (SEQ ID NO:4197) HIF-1α-124 21 nt Targ: 5′-CTGCCTCAGCTCCTCAGTGCA-3′ (SEQ ID NO:4198) HIF-1α-126 21 nt Targ: 5′-GCCTCAGCTCCTCAGTGCACA-3′ (SEQ ID NO:4199) HIF-1α-130 21 nt Targ: 5′-CAGCTCCTCAGTGCACAGTGC-3′ (SEQ ID NO:4200) HIF-1α-131 21 nt Targ: 5′-AGCTCCTCAGTGCACAGTGCT-3′ (SEQ ID NO:4201) HIF-1α-147 21 nt Targ: 5′-GTGCTGCCTCGTCTGAGGGGA-3′ (SEQ ID NO:4202) HIF-1α-265 21 nt Targ: 5′-GATTGCCGCCCGCTTCTCTCT-3′ (SEQ ID NO:4203) HIF-1α-267 21 nt Targ: 5′-TTGCCGCCCGCTTCTCTCTAG-3′ (SEQ ID NO:4204) HIF-1α-268 21 nt Targ: 5′-TGCCGCCCGCTTCTCTCTAGT-3′ (SEQ ID NO:4205) HIF-1α-292 21 nt Targ: 5′-ACGAGGGGTTTCCCGCCTCGC-3′ (SEQ ID NO:4206) HIF-1α-319 21 nt Targ: 5′-ACCTCTGGACTTGCCTTTCCT-3′ (SEQ ID NO:4207) HIF-1α-322 21 nt Targ: 5′-TCTGGACTTGCCTTTCCTTCT-3′ (SEQ ID NO:4208) HIF-1α-324 21 nt Targ: 5′-TGGACTTGCCTTTCCTTCTCT-3′ (SEQ ID NO:4209) HIF-1α-327 21 nt Targ: 5′-ACTTGCCTTTCCTTCTCTTCT-3′ (SEQ ID NO:4210) HIF-1α-329 21 nt Targ: 5′-TTGCCTTTCCTTCTCTTCTCC-3′ (SEQ ID NO:4211) HIF-1α-330 21 nt Targ: 5′-TGCCTTTCCTTCTCTTCTCCG-3′ (SEQ ID NO:4212) HIF-1α-331 21 nt Targ: 5′-GCCTTTCCTTCTCTTCTCCGC-3′ (SEQ ID NO:4213) HIF-1α-342 21 nt Targ: 5′-TCTTCTCCGCGTGTGGAGGGA-3′ (SEQ ID NO:4214) HIF-1α-344 21 nt Targ: 5′-TTCTCCGCGTGTGGAGGGAGC-3′ (SEQ ID NO:4215) HIF-1α-346 21 nt Targ: 5′-CTCCGCGTGTGGAGGGAGCCA-3′ (SEQ ID NO:4216) HIF-1α-359 21 nt Targ: 5′-GGGAGCCAGCGCTTAGGCCGG-3′ (SEQ ID NO:4217) HIF-1α-403 21 nt Targ: 5′-GTGAAGACATCGCGGGGACCG-3′ (SEQ ID NO:4218) HIF-1α-422 21 nt Targ: 5′-CGATTCACCATGGAGGGCGCC-3′ (SEQ ID NO:4219) HIF-1α-427 21 nt Targ: 5′-CACCATGGAGGGCGCCGGCGG-3′ (SEQ ID NO:4220) HIF-1α-429 21 nt Targ: 5′-CCATGGAGGGCGCCGGCGGCG-3′ (SEQ ID NO:4221) HIF-1α-448 21 nt Targ: 5′-CGCGAACGACAAGAAAAAGAT-3′ (SEQ ID NO:4222) HIF-1α-455 21 nt Targ: 5′-GACAAGAAAAAGATAAGTTCT-3′ (SEQ ID NO:4223) HIF-1α-469 21 nt Targ: 5′-AAGTTCTGAACGTCGAAAAGA-3′ (SEQ ID NO:4224) HIF-1α-471 21 nt Targ: 5′-GTTCTGAACGTCGAAAAGAAA-3′ (SEQ ID NO:4225) HIF-1α-473 21 nt Targ: 5′-TCTGAACGTCGAAAAGAAAAG-3′ (SEQ ID NO:4226) HIF-1α-475 21 nt Targ: 5′-TGAACGTCGAAAAGAAAAGTC-3′ (SEQ ID NO:4227) HIF-1α-525 21 nt Targ: 5′-AAGAATCTGAAGTTTTTTATG-3′ (SEQ ID NO:4228) HIF-1α-528 21 nt Targ: 5′-AATCTGAAGTTTTTTATGAGC-3′ (SEQ ID NO:4229) HIF-1α-530 21 nt Targ: 5′-TCTGAAGTTTTTTATGAGCTT-3′ (SEQ ID NO:4230) HIF-1α-532 21 nt Targ: 5′-TGAAGTTTTTTATGAGCTTGC-3′ (SEQ ID NO:4231) HIF-1α-534 21 nt Targ: 5′-AAGTTTTTTATGAGCTTGCTC-3′ (SEQ ID NO:4232) HIF-1α-536 21 nt Targ: 5′-GTTTTTTATGAGCTTGCTCAT-3′ (SEQ ID NO:4233) HIF-1α-538 21 nt Targ: 5′-TTTTTATGAGCTTGCTCATCA-3′ (SEQ ID NO:4234) HIF-1α-540 21 nt Targ: 5′-TTTATGAGCTTGCTCATCAGT-3′ (SEQ ID NO:4235) HIF-1α-542 21 nt Targ: 5′-TATGAGCTTGCTCATCAGTTG-3′ (SEQ ID NO:4236) HIF-1α-544 21 nt Targ: 5′-TGAGCTTGCTCATCAGTTGCC-3′ (SEQ ID NO:4237) HIF-1α-546 21 nt Targ: 5′-AGCTTGCTCATCAGTTGCCAC-3′ (SEQ ID NO:4238) HIF-1α-548 21 nt Targ: 5′-CTTGCTCATCAGTTGCCACTT-3′ (SEQ ID NO:4239) HIF-1α-550 21 nt Targ: 5′-TGCTCATCAGTTGCCACTTCC-3′ (SEQ ID NO:4240) HIF-1α-562 21 nt Targ: 5′-GCCACTTCCACATAATGTGAG-3′ (SEQ ID NO:4241) HIF-1α-642 21 nt Targ: 5′-AACTTCTGGATGCTGGTGATT-3′ (SEQ ID NO:4242) HIF-1α-644 21 nt Targ: 5′-CTTCTGGATGCTGGTGATTTG-3′ (SEQ ID NO:4243) HIF-1α-645 21 nt Targ: 5′-TTCTGGATGCTGGTGATTTGG-3′ (SEQ ID NO:4244) HIF-1α-665 21 nt Targ: 5′-GATATTGAAGATGACATGAAA-3′ (SEQ ID NO:4245) HIF-1α-691 21 nt Targ: 5′-GATGAATTGCTTTTATTTGAA-3′ (SEQ ID NO:4246) HIF-1α-707 21 nt Targ: 5′-TTGAAAGCCTTGGATGGTTTT-3′ (SEQ ID NO:4247) HIF-1α-711 21 nt Targ: 5′-AAGCCTTGGATGGTTTTGTTA-3′ (SEQ ID NO:4248) HIF-1α-713 21 nt Targ: 5′-GCCTTGGATGGTTTTGTTATG-3′ (SEQ ID NO:4249) HIF-1α-715 21 nt Targ: 5′-CTTGGATGGTTTTGTTATGGT-3′ (SEQ ID NO:4250) HIF-1α-717 21 nt Targ: 5′-TGGATGGTTTTGTTATGGTTC-3′ (SEQ ID NO:4251) HIF-1α-756 21 nt Targ: 5′-TGATTTACATTTCTGATAATG-3′ (SEQ ID NO:4252) HIF-1α-790 21 nt Targ: 5′-GGGATTAACTCAGTTTGAACT-3′ (SEQ ID NO:4253) HIF-1α-793 21 nt Targ: 5′-ATTAACTCAGTTTGAACTAAC-3′ (SEQ ID NO:4254) HIF-1α-824 21 nt Targ: 5′-GTGTTTGATTTTACTCATCCA-3′ (SEQ ID NO:4255) HIF-1α-826 21 nt Targ: 5′-GTTTGATTTTACTCATCCATG-3′ (SEQ ID NO:4256) HIF-1α-828 21 nt Targ: 5′-TTGATTTTACTCATCCATGTG-3′ (SEQ ID NO:4257) HIF-1α-830 21 nt Targ: 5′-GATTTTACTCATCCATGTGAC-3′ (SEQ ID NO:4258) HIF-1α-832 21 nt Targ: 5′-TTTTACTCATCCATGTGACCA-3′ (SEQ ID NO:4259) HIF-1α-834 21 nt Targ: 5′-TTACTCATCCATGTGACCATG-3′ (SEQ ID NO:4260) HIF-1α-836 21 nt Targ: 5′-ACTCATCCATGTGACCATGAG-3′ (SEQ ID NO:4261) HIF-1α-838 21 nt Targ: 5′-TCATCCATGTGACCATGAGGA-3′ (SEQ ID NO:4262) HIF-1α-840 21 nt Targ: 5′-ATCCATGTGACCATGAGGAAA-3′ (SEQ ID NO:4263) HIF-1α-842 21 nt Targ: 5′-CCATGTGACCATGAGGAAATG-3′ (SEQ ID NO:4264) HIF-1α-844 21 nt Targ: 5′-ATGTGACCATGAGGAAATGAG-3′ (SEQ ID NO:4265) HIF-1α-846 21 nt Targ: 5′-GTGACCATGAGGAAATGAGAG-3′ (SEQ ID NO:4266) HIF-1α-848 21 nt Targ: 5′-GACCATGAGGAAATGAGAGAA-3′ (SEQ ID NO:4267) HIF-1α-850 21 nt Targ: 5′-CCATGAGGAAATGAGAGAAAT-3′ (SEQ ID NO:4268) HIF-1α-852 21 nt Targ: 5′-ATGAGGAAATGAGAGAAATGC-3′ (SEQ ID NO:4269) HIF-1α-921 21 nt Targ: 5′-AGCGAAGCTTTTTTCTCAGAA-3′ (SEQ ID NO:4270) HIF-1α-925 21 nt Targ: 5′-AAGCTTTTTTCTCAGAATGAA-3′ (SEQ ID NO:4271) HIF-1α-927 21 nt Targ: 5′-GCTTTTTTCTCAGAATGAAGT-3′ (SEQ ID NO:4272) HIF-1α-1029 21 nt Targ: 5′-TATATGATACCAACAGTAACC-3′ (SEQ ID NO:4273) HIF-1α-1031 21 nt Targ: 5′-TATGATACCAACAGTAACCAA-3′ (SEQ ID NO:4274) HIF-1α-1033 21 nt Targ: 5′-TGATACCAACAGTAACCAACC-3′ (SEQ ID NO:4275) HIF-1α-1035 21 nt Targ: 5′-ATACCAACAGTAACCAACCTC-3′ (SEQ ID NO:4276) HIF-1α-1037 21 nt Targ: 5′-ACCAACAGTAACCAACCTCAG-3′ (SEQ ID NO:4277) HIF-1α-1039 21 nt Targ: 5′-CAACAGTAACCAACCTCAGTG-3′ (SEQ ID NO:4278) HIF-1α-1041 21 nt Targ: 5′-ACAGTAACCAACCTCAGTGTG-3′ (SEQ ID NO:4279) HIF-1α-1043 21 nt Targ: 5′-AGTAACCAACCTCAGTGTGGG-3′ (SEQ ID NO:4280) HIF-1α-1045 21 nt Targ: 5′-TAACCAACCTCAGTGTGGGTA-3′ (SEQ ID NO:4281) HIF-1α-1074 21 nt Targ: 5′-CACCTATGACCTGCTTGGTGC-3′ (SEQ ID NO:4282) HIF-1α-1075 21 nt Targ: 5′-ACCTATGACCTGCTTGGTGCT-3′ (SEQ ID NO:4283) HIF-1α-1077 21 nt Targ: 5′-CTATGACCTGCTTGGTGCTGA-3′ (SEQ ID NO:4284) HIF-1α-1084 21 nt Targ: 5′-CTGCTTGGTGCTGATTTGTGA-3′ (SEQ ID NO:4285) HIF-1α-1086 21 nt Targ: 5′-GCTTGGTGCTGATTTGTGAAC-3′ (SEQ ID NO:4286) HIF-1α-1088 21 nt Targ: 5′-TTGGTGCTGATTTGTGAACCC-3′ (SEQ ID NO:4287) HIF-1α-1090 21 nt Targ: 5′-GGTGCTGATTTGTGAACCCAT-3′ (SEQ ID NO:4288) HIF-1α-1092 21 nt Targ: 5′-TGCTGATTTGTGAACCCATTC-3′ (SEQ ID NO:4289) HIF-1α-1094 21 nt Targ: 5′-CTGATTTGTGAACCCATTCCT-3′ (SEQ ID NO:4290) HIF-1α-1096 21 nt Targ: 5′-GATTTGTGAACCCATTCCTCA-3′ (SEQ ID NO:4291) HIF-1α-1120 21 nt Targ: 5′-ATCAAATATTGAAATTCCTTT-3′ (SEQ ID NO:4292) HIF-1α-1122 21 nt Targ: 5′-CAAATATTGAAATTCCTTTAG-3′ (SEQ ID NO:4293) HIF-1α-1124 21 nt Targ: 5′-AATATTGAAATTCCTTTAGAT-3′ (SEQ ID NO:4294) HIF-1α-1126 21 nt Targ: 5′-TATTGAAATTCCTTTAGATAG-3′ (SEQ ID NO:4295) HIF-1α-1128 21 nt Targ: 5′-TTGAAATTCCTTTAGATAGCA-3′ (SEQ ID NO:4296) HIF-1α-1130 21 nt Targ: 5′-GAAATTCCTTTAGATAGCAAG-3′ (SEQ ID NO:4297) HIF-1α-1132 21 nt Targ: 5′-AATTCCTTTAGATAGCAAGAC-3′ (SEQ ID NO:4298) HIF-1α-1166 21 nt Targ: 5′-CACAGCCTGGATATGAAATTT-3′ (SEQ ID NO:4299) HIF-1α-1174 21 nt Targ: 5′-GGATATGAAATTTTCTTATTG-3′ (SEQ ID NO:4300) HIF-1α-1243 21 nt Targ: 5′-AGGCCGCTCAATTTATGAATA-3′ (SEQ ID NO:4301) HIF-1α-1245 21 nt Targ: 5′-GCCGCTCAATTTATGAATATT-3′ (SEQ ID NO:4302) HIF-1α-1247 21 nt Targ: 5′-CGCTCAATTTATGAATATTAT-3′ (SEQ ID NO:4303) HIF-1α-1249 21 nt Targ: 5′-CTCAATTTATGAATATTATCA-3′ (SEQ ID NO:4304) HIF-1α-1251 21 nt Targ: 5′-CAATTTATGAATATTATCATG-3′ (SEQ ID NO:4305) HIF-1α-1253 21 nt Targ: 5′-ATTTATGAATATTATCATGCT-3′ (SEQ ID NO:4306) HIF-1α-1255 21 nt Targ: 5′-TTATGAATATTATCATGCTTT-3′ (SEQ ID NO:4307) HIF-1α-1257 21 nt Targ: 5′-ATGAATATTATCATGCTTTGG-3′ (SEQ ID NO:4308) HIF-1α-1262 21 nt Targ: 5′-TATTATCATGCTTTGGACTCT-3′ (SEQ ID NO:4309) HIF-1α-1265 21 nt Targ: 5′-TATCATGCTTTGGACTCTGAT-3′ (SEQ ID NO:4310) HIF-1α-1268 21 nt Targ: 5′-CATGCTTTGGACTCTGATCAT-3′ (SEQ ID NO:4311) HIF-1α-1271 21 nt Targ: 5′-GCTTTGGACTCTGATCATCTG-3′ (SEQ ID NO:4312) HIF-1α-1278 21 nt Targ: 5′-ACTCTGATCATCTGACCAAAA-3′ (SEQ ID NO:4313) HIF-1α-1280 21 nt Targ: 5′-TCTGATCATCTGACCAAAACT-3′ (SEQ ID NO:4314) HIF-1α-1282 21 nt Targ: 5′-TGATCATCTGACCAAAACTCA-3′ (SEQ ID NO:4315) HIF-1α-1303 21 nt Targ: 5′-TCATGATATGTTTACTAAAGG-3′ (SEQ ID NO:4316) HIF-1α-1305 21 nt Targ: 5′-ATGATATGTTTACTAAAGGAC-3′ (SEQ ID NO:4317) HIF-1α-1307 21 nt Targ: 5′-GATATGTTTACTAAAGGACAA-3′ (SEQ ID NO:4318) HIF-1α-1309 21 nt Targ: 5′-TATGTTTACTAAAGGACAAGT-3′ (SEQ ID NO:4319) HIF-1α-1311 21 nt Targ: 5′-TGTTTACTAAAGGACAAGTCA-3′ (SEQ ID NO:4320) HIF-1α-1313 21 nt Targ: 5′-TTTACTAAAGGACAAGTCACC-3′ (SEQ ID NO:4321) HIF-1α-1315 21 nt Targ: 5′-TACTAAAGGACAAGTCACCAC-3′ (SEQ ID NO:4322) HIF-1α-1317 21 nt Targ: 5′-CTAAAGGACAAGTCACCACAG-3′ (SEQ ID NO:4323) HIF-1α-1319 21 nt Targ: 5′-AAAGGACAAGTCACCACAGGA-3′ (SEQ ID NO:4324) HIF-1α-1321 21 nt Targ: 5′-AGGACAAGTCACCACAGGACA-3′ (SEQ ID NO:4325) HIF-1α-1323 21 nt Targ: 5′-GACAAGTCACCACAGGACAGT-3′ (SEQ ID NO:4326) HIF-1α-1325 21 nt Targ: 5′-CAAGTCACCACAGGACAGTAC-3′ (SEQ ID NO:4327) HIF-1α-1327 21 nt Targ: 5′-AGTCACCACAGGACAGTACAG-3′ (SEQ ID NO:4328) HIF-1α-1329 21 nt Targ: 5′-TCACCACAGGACAGTACAGGA-3′ (SEQ ID NO:4329) HIF-1α-1331 21 nt Targ: 5′-ACCACAGGACAGTACAGGATG-3′ (SEQ ID NO:4330) HIF-1α-1333 21 nt Targ: 5′-CACAGGACAGTACAGGATGCT-3′ (SEQ ID NO:4331) HIF-1α-1335 21 nt Targ: 5′-CAGGACAGTACAGGATGCTTG-3′ (SEQ ID NO:4332) HIF-1α-1337 21 nt Targ: 5′-GGACAGTACAGGATGCTTGCC-3′ (SEQ ID NO:4333) HIF-1α-1339 21 nt Targ: 5′-ACAGTACAGGATGCTTGCCAA-3′ (SEQ ID NO:4334) HIF-1α-1341 21 nt Targ: 5′-AGTACAGGATGCTTGCCAAAA-3′ (SEQ ID NO:4335) HIF-1α-1343 21 nt Targ: 5′-TACAGGATGCTTGCCAAAAGA-3′ (SEQ ID NO:4336) HIF-1α-1345 21 nt Targ: 5′-CAGGATGCTTGCCAAAAGAGG-3′ (SEQ ID NO:4337) HIF-1α-1347 21 nt Targ: 5′-GGATGCTTGCCAAAAGAGGTG-3′ (SEQ ID NO:4338) HIF-1α-1349 21 nt Targ: 5′-ATGCTTGCCAAAAGAGGTGGA-3′ (SEQ ID NO:4339) HIF-1α-1351 21 nt Targ: 5′-GCTTGCCAAAAGAGGTGGATA-3′ (SEQ ID NO:4340) HIF-1α-1353 21 nt Targ: 5′-TTGCCAAAAGAGGTGGATATG-3′ (SEQ ID NO:4341) HIF-1α-1355 21 nt Targ: 5′-GCCAAAAGAGGTGGATATGTC-3′ (SEQ ID NO:4342) HIF-1α-1357 21 nt Targ: 5′-CAAAAGAGGTGGATATGTCTG-3′ (SEQ ID NO:4343) HIF-1α-1359 21 nt Targ: 5′-AAAGAGGTGGATATGTCTGGG-3′ (SEQ ID NO:4344) HIF-1α-1361 21 nt Targ: 5′-AGAGGTGGATATGTCTGGGTT-3′ (SEQ ID NO:4345) HIF-1α-1363 21 nt Targ: 5′-AGGTGGATATGTCTGGGTTGA-3′ (SEQ ID NO:4346) HIF-1α-1365 21 nt Targ: 5′-GTGGATATGTCTGGGTTGAAA-3′ (SEQ ID NO:4347) HIF-1α-1367 21 nt Targ: 5′-GGATATGTCTGGGTTGAAACT-3′ (SEQ ID NO:4348) HIF-1α-1369 21 nt Targ: 5′-ATATGTCTGGGTTGAAACTCA-3′ (SEQ ID NO:4349) HIF-1α-1371 21 nt Targ: 5′-ATGTCTGGGTTGAAACTCAAG-3′ (SEQ ID NO:4350) HIF-1α-1373 21 nt Targ: 5′-GTCTGGGTTGAAACTCAAGCA-3′ (SEQ ID NO:4351) HIF-1α-1375 21 nt Targ: 5′-CTGGGTTGAAACTCAAGCAAC-3′ (SEQ ID NO:4352) HIF-1α-1377 21 nt Targ: 5′-GGGTTGAAACTCAAGCAACTG-3′ (SEQ ID NO:4353) HIF-1α-1379 21 nt Targ: 5′-GTTGAAACTCAAGCAACTGTC-3′ (SEQ ID NO:4354) HIF-1α-1381 21 nt Targ: 5′-TGAAACTCAAGCAACTGTCAT-3′ (SEQ ID NO:4355) HIF-1α-1383 21 nt Targ: 5′-AAACTCAAGCAACTGTCATAT-3′ (SEQ ID NO:4356) HIF-1α-1385 21 nt Targ: 5′-ACTCAAGCAACTGTCATATAT-3′ (SEQ ID NO:4357) HIF-1α-1387 21 nt Targ: 5′-TCAAGCAACTGTCATATATAA-3′ (SEQ ID NO:4358) HIF-1α-1456 21 nt Targ: 5′-GAGTGGTATTATTCAGCACGA-3′ (SEQ ID NO:4359) HIF-1α-1458 21 nt Targ: 5′-GTGGTATTATTCAGCACGACT-3′ (SEQ ID NO:4360) HIF-1α-1460 21 nt Targ: 5′-GGTATTATTCAGCACGACTTG-3′ (SEQ ID NO:4361) HIF-1α-1462 21 nt Targ: 5′-TATTATTCAGCACGACTTGAT-3′ (SEQ ID NO:4362) HIF-1α-1464 21 nt Targ: 5′-TTATTCAGCACGACTTGATTT-3′ (SEQ ID NO:4363) HIF-1α-1466 21 nt Targ: 5′-ATTCAGCACGACTTGATTTTC-3′ (SEQ ID NO:4364) HIF-1α-1468 21 nt Targ: 5′-TCAGCACGACTTGATTTTCTC-3′ (SEQ ID NO:4365) HIF-1α-1470 21 nt Targ: 5′-AGCACGACTTGATTTTCTCCC-3′ (SEQ ID NO:4366) HIF-1α-1472 21 nt Targ: 5′-CACGACTTGATTTTCTCCCTT-3′ (SEQ ID NO:4367) HIF-1α-1474 21 nt Targ: 5′-CGACTTGATTTTCTCCCTTCA-3′ (SEQ ID NO:4368) HIF-1α-1476 21 nt Targ: 5′-ACTTGATTTTCTCCCTTCAAC-3′ (SEQ ID NO:4369) HIF-1α-1478 21 nt Targ: 5′-TTGATTTTCTCCCTTCAACAA-3′ (SEQ ID NO:4370) HIF-1α-1480 21 nt Targ: 5′-GATTTTCTCCCTTCAACAAAC-3′ (SEQ ID NO:4371) HIF-1α-1482 21 nt Targ: 5′-TTTTCTCCCTTCAACAAACAG-3′ (SEQ ID NO:4372) HIF-1α-1519 21 nt Targ: 5′-GGTTGAATCTTCAGATATGAA-3′ (SEQ ID NO:4373) HIF-1α-1552 21 nt Targ: 5′-ATTCACCAAAGTTGAATCAGA-3′ (SEQ ID NO:4374) HIF-1α-1572 21 nt Targ: 5′-AAGATACAAGTAGCCTCTTTG-3′ (SEQ ID NO:4375) HIF-1α-1648 21 nt Targ: 5′-CACAATCATATCTTTAGATTT-3′ (SEQ ID NO:4376) HIF-1α-1709 21 nt Targ: 5′-GAAGTACCATTATATAATGAT-3′ (SEQ ID NO:4377) HIF-1α-1714 21 nt Targ: 5′-ACCATTATATAATGATGTAAT-3′ (SEQ ID NO:4378) HIF-1α-1786 21 nt Targ: 5′-ATTACCCACCGCTGAAACGCC-3′ (SEQ ID NO:4379) HIF-1α-1804 21 nt Targ: 5′-GCCAAAGCCACTTCGAAGTAG-3′ (SEQ ID NO:4380) HIF-1α-1806 21 nt Targ: 5′-CAAAGCCACTTCGAAGTAGTG-3′ (SEQ ID NO:4381) HIF-1α-1808 21 nt Targ: 5′-AAGCCACTTCGAAGTAGTGCT-3′ (SEQ ID NO:4382) HIF-1α-1810 21 nt Targ: 5′-GCCACTTCGAAGTAGTGCTGA-3′ (SEQ ID NO:4383) HIF-1α-1814 21 nt Targ: 5′-CTTCGAAGTAGTGCTGACCCT-3′ (SEQ ID NO:4384) HIF-1α-1845 21 nt Targ: 5′-AAGAAGTTGCATTAAAATTAG-3′ (SEQ ID NO:4385) HIF-1α-1936 21 nt Targ: 5′-CGATGGAAGCACTAGACAAAG-3′ (SEQ ID NO:4386) HIF-1α-1938 21 nt Targ: 5′-ATGGAAGCACTAGACAAAGTT-3′ (SEQ ID NO:4387) HIF-1α-1940 21 nt Targ: 5′-GGAAGCACTAGACAAAGTTCA-3′ (SEQ ID NO:4388) HIF-1α-1942 21 nt Targ: 5′-AAGCACTAGACAAAGTTCACC-3′ (SEQ ID NO:4389) HIF-1α-1944 21 nt Targ: 5′-GCACTAGACAAAGTTCACCTG-3′ (SEQ ID NO:4390) HIF-1α-1946 21 nt Targ: 5′-ACTAGACAAAGTTCACCTGAG-3′ (SEQ ID NO:4391) HIF-1α-1977 21 nt Targ: 5′-CCAGTGAATATTGTTTTTATG-3′ (SEQ ID NO:4392) HIF-1α-1985 21 nt Targ: 5′-TATTGTTTTTATGTGGATAGT-3′ (SEQ ID NO:4393) HIF-1α-2034 21 nt Targ: 5′-TGGTAGAAAAACTTTTTGCTG-3′ (SEQ ID NO:4394) HIF-1α-2116 21 nt Targ: 5′-AGCTCCCTATATCCCAATGGA-3′ (SEQ ID NO:4395) HIF-1α-2118 21 nt Targ: 5′-CTCCCTATATCCCAATGGATG-3′ (SEQ ID NO:4396) HIF-1α-2120 21 nt Targ: 5′-CCCTATATCCCAATGGATGAT-3′ (SEQ ID NO:4397) HIF-1α-2122 21 nt Targ: 5′-CTATATCCCAATGGATGATGA-3′ (SEQ ID NO:4398) HIF-1α-2161 21 nt Targ: 5′-CGATCAGTTGTCACCATTAGA-3′ (SEQ ID NO:4399) HIF-1α-2185 21 nt Targ: 5′-CAGTTCCGCAAGCCCTGAAAG-3′ (SEQ ID NO:4400) HIF-1α-2187 21 nt Targ: 5′-GTTCCGCAAGCCCTGAAAGCG-3′ (SEQ ID NO:4401) HIF-1α-2290 21 nt Targ: 5′-CACTGATGAATTAAAAACAGT-3′ (SEQ ID NO:4402) HIF-1α-2326 21 nt Targ: 5′-GGAAGACATTAAAATATTGAT-3′ (SEQ ID NO:4403) HIF-1α-2452 21 nt Targ: 5′-AGGAGTCATAGAACAGACAGA-3′ (SEQ ID NO:4404) HIF-1α-2555 21 nt Targ: 5′-AAGATACTAGCTTTGCAGAAT-3′ (SEQ ID NO:4405) HIF-1α-2577 21 nt Targ: 5′-CTCAGAGAAAGCGAAAAATGG-3′ (SEQ ID NO:4406) HIF-1α-2584 21 nt Targ: 5′-AAAGCGAAAAATGGAACATGA-3′ (SEQ ID NO:4407) HIF-1α-2586 21 nt Targ: 5′-AGCGAAAAATGGAACATGATG-3′ (SEQ ID NO:4408) HIF-1α-2618 21 nt Targ: 5′-CAAGCAGTAGGAATTGGAACA-3′ (SEQ ID NO:4409) HIF-1α-2705 21 nt Targ: 5′-AAATCTAGTGAACAGAATGGA-3′ (SEQ ID NO:4410) HIF-1α-2730 21 nt Targ: 5′-AGCAAAAGACAATTATTTTAA-3′ (SEQ ID NO:4411) HIF-1α-2796 21 nt Targ: 5′-AAAGTGGATTACCACAGCTGA-3′ (SEQ ID NO:4412) HIF-1α-2798 21 nt Targ: 5′-AGTGGATTACCACAGCTGACC-3′ (SEQ ID NO:4413) HIF-1α-2800 21 nt Targ: 5′-TGGATTACCACAGCTGACCAG-3′ (SEQ ID NO:4414) HIF-1α-2802 21 nt Targ: 5′-GATTACCACAGCTGACCAGTT-3′ (SEQ ID NO:4415) HIF-1α-2823 21 nt Targ: 5′-ATGATTGTGAAGTTAATGCTC-3′ (SEQ ID NO:4416) HIF-1α-2844 21 nt Targ: 5′-CTATACAAGGCAGCAGAAACC-3′ (SEQ ID NO:4417) HIF-1α-2846 21 nt Targ: 5′-ATACAAGGCAGCAGAAACCTA-3′ (SEQ ID NO:4418) HIF-1α-2848 21 nt Targ: 5′-ACAAGGCAGCAGAAACCTACT-3′ (SEQ ID NO:4419) HIF-1α-2850 21 nt Targ: 5′-AAGGCAGCAGAAACCTACTGC-3′ (SEQ ID NO:4420) HIF-1α-2852 21 nt Targ: 5′-GGCAGCAGAAACCTACTGCAG-3′ (SEQ ID NO:4421) HIF-1α-2854 21 nt Targ: 5′-CAGCAGAAACCTACTGCAGGG-3′ (SEQ ID NO:4422) HIF-1α-2856 21 nt Targ: 5′-GCAGAAACCTACTGCAGGGTG-3′ (SEQ ID NO:4423) HIF-1α-2858 21 nt Targ: 5′-AGAAACCTACTGCAGGGTGAA-3′ (SEQ ID NO:4424) HIF-1α-2860 21 nt Targ: 5′-AAACCTACTGCAGGGTGAAGA-3′ (SEQ ID NO:4425) HIF-1α-2862 21 nt Targ: 5′-ACCTACTGCAGGGTGAAGAAT-3′ (SEQ ID NO:4426) HIF-1α-2864 21 nt Targ: 5′-CTACTGCAGGGTGAAGAATTA-3′ (SEQ ID NO:4427) HIF-1α-2866 21 nt Targ: 5′-ACTGCAGGGTGAAGAATTACT-3′ (SEQ ID NO:4428) HIF-1α-2868 21 nt Targ: 5′-TGCAGGGTGAAGAATTACTCA-3′ (SEQ ID NO:4429) HIF-1α-2870 21 nt Targ: 5′-CAGGGTGAAGAATTACTCAGA-3′ (SEQ ID NO:4430) HIF-1α-2872 21 nt Targ: 5′-GGGTGAAGAATTACTCAGAGC-3′ (SEQ ID NO:4431) HIF-1α-2874 21 nt Targ: 5′-GTGAAGAATTACTCAGAGCTT-3′ (SEQ ID NO:4432) HIF-1α-2876 21 nt Targ: 5′-GAAGAATTACTCAGAGCTTTG-3′ (SEQ ID NO:4433) HIF-1α-2878 21 nt Targ: 5′-AGAATTACTCAGAGCTTTGGA-3′ (SEQ ID NO:4434) HIF-1α-2880 21 nt Targ: 5′-AATTACTCAGAGCTTTGGATC-3′ (SEQ ID NO:4435) HIF-1α-2882 21 nt Targ: 5′-TTACTCAGAGCTTTGGATCAA-3′ (SEQ ID NO:4436) HIF-1α-2884 21 nt Targ: 5′-ACTCAGAGCTTTGGATCAAGT-3′ (SEQ ID NO:4437) HIF-1α-2886 21 nt Targ: 5′-TCAGAGCTTTGGATCAAGTTA-3′ (SEQ ID NO:4438) HIF-1α-2888 21 nt Targ: 5′-AGAGCTTTGGATCAAGTTAAC-3′ (SEQ ID NO:4439) HIF-1α-2890 21 nt Targ: 5′-AGCTTTGGATCAAGTTAACTG-3′ (SEQ ID NO:4440) HIF-1α-2892 21 nt Targ: 5′-CTTTGGATCAAGTTAACTGAG-3′ (SEQ ID NO:4441) HIF-1α-2895 21 nt Targ: 5′-TGGATCAAGTTAACTGAGCTT-3′ (SEQ ID NO:4442) HIF-1α-2906 21 nt Targ: 5′-AACTGAGCTTTTTCTTAATTT-3′ (SEQ ID NO:4443) HIF-1α-2910 21 nt Targ: 5′-GAGCTTTTTCTTAATTTCATT-3′ (SEQ ID NO:4444) HIF-1α-2919 21 nt Targ: 5′-CTTAATTTCATTCCTTTTTTT-3′ (SEQ ID NO:4445) HIF-1α-2925 21 nt Targ: 5′-TTCATTCCTTTTTTTGGACAC-3′ (SEQ ID NO:4446) HIF-1α-2933 21 nt Targ: 5′-TTTTTTTGGACACTGGTGGCT-3′ (SEQ ID NO:4447) HIF-1α-2935 21 nt Targ: 5′-TTTTTGGACACTGGTGGCTCA-3′ (SEQ ID NO:4448) HIF-1α-2963 21 nt Targ: 5′-AAGCAGTCTATTTATATTTTC-3′ (SEQ ID NO:4449) HIF-1α-2965 21 nt Targ: 5′-GCAGTCTATTTATATTTTCTA-3′ (SEQ ID NO:4450) HIF-1α-2970 21 nt Targ: 5′-CTATTTATATTTTCTACATCT-3′ (SEQ ID NO:4451) HIF-1α-2986 21 nt Targ: 5′-CATCTAATTTTAGAAGCCTGG-3′ (SEQ ID NO:4452) HIF-1α-2988 21 nt Targ: 5′-TCTAATTTTAGAAGCCTGGCT-3′ (SEQ ID NO:4453) HIF-1α-2990 21 nt Targ: 5′-TAATTTTAGAAGCCTGGCTAC-3′ (SEQ ID NO:4454) HIF-1α-2992 21 nt Targ: 5′-ATTTTAGAAGCCTGGCTACAA-3′ (SEQ ID NO:4455) HIF-1α-2994 21 nt Targ: 5′-TTTAGAAGCCTGGCTACAATA-3′ (SEQ ID NO:4456) HIF-1α-2996 21 nt Targ: 5′-TAGAAGCCTGGCTACAATACT-3′ (SEQ ID NO:4457) HIF-1α-2998 21 nt Targ: 5′-GAAGCCTGGCTACAATACTGC-3′ (SEQ ID NO:4458) HIF-1α-3000 21 nt Targ: 5′-AGCCTGGCTACAATACTGCAC-3′ (SEQ ID NO:4459) HIF-1α-3002 21 nt Targ: 5′-CCTGGCTACAATACTGCACAA-3′ (SEQ ID NO:4460) HIF-1α-3004 21 nt Targ: 5′-TGGCTACAATACTGCACAAAC-3′ (SEQ ID NO:4461) HIF-1α-3055 21 nt Targ: 5′-CTTAATTTACATTAATGCTCT-3′ (SEQ ID NO:4462) HIF-1α-3065 21 nt Targ: 5′-ATTAATGCTCTTTTTTAGTAT-3′ (SEQ ID NO:4463) HIF-1α-3067 21 nt Targ: 5′-TAATGCTCTTTTTTAGTATGT-3′ (SEQ ID NO:4464) HIF-1α-3068 21 nt Targ: 5′-AATGCTCTTTTTTAGTATGTT-3′ (SEQ ID NO:4465) HIF-1α-3077 21 nt Targ: 5′-TTTTAGTATGTTCTTTAATGC-3′ (SEQ ID NO:4466) HIF-1α-3081 21 nt Targ: 5′-AGTATGTTCTTTAATGCTGGA-3′ (SEQ ID NO:4467) HIF-1α-3088 21 nt Targ: 5′-TCTTTAATGCTGGATCACAGA-3′ (SEQ ID NO:4468) HIF-1α-3093 21 nt Targ: 5′-AATGCTGGATCACAGACAGCT-3′ (SEQ ID NO:4469) HIF-1α-3110 21 nt Targ: 5′-AGCTCATTTTCTCAGTTTTTT-3′ (SEQ ID NO:4470) HIF-1α-3167 21 nt Targ: 5′-AAAAAATGCACCTTTTTATTT-3′ (SEQ ID NO:4471) HIF-1α-3169 21 nt Targ: 5′-AAAATGCACCTTTTTATTTAT-3′ (SEQ ID NO:4472) HIF-1α-3171 21 nt Targ: 5′-AATGCACCTTTTTATTTATTT-3′ (SEQ ID NO:4473) HIF-1α-3173 21 nt Targ: 5′-TGCACCTTTTTATTTATTTAT-3′ (SEQ ID NO:4474) HIF-1α-3175 21 nt Targ: 5′-CACCTTTTTATTTATTTATTT-3′ (SEQ ID NO:4475) HIF-1α-3177 21 nt Targ: 5′-CCTTTTTATTTATTTATTTTT-3′ (SEQ ID NO:4476) HIF-1α-3179 21 nt Targ: 5′-TTTTTATTTATTTATTTTTGG-3′ (SEQ ID NO:4477) HIF-1α-3215 21 nt Targ: 5′-CTTTTTCGAATTATTTTTAAG-3′ (SEQ ID NO:4478) HIF-1α-3241 21 nt Targ: 5′-GCCAATATAATTTTTGTAAGA-3′ (SEQ ID NO:4479) HIF-1α-3274 21 nt Targ: 5′-TTCATCATGATCATAGGCAGT-3′ (SEQ ID NO:4480) HIF-1α-3276 21 nt Targ: 5′-CATCATGATCATAGGCAGTTG-3′ (SEQ ID NO:4481) HIF-1α-3278 21 nt Targ: 5′-TCATGATCATAGGCAGTTGAA-3′ (SEQ ID NO:4482) HIF-1α-3280 21 nt Targ: 5′-ATGATCATAGGCAGTTGAAAA-3′ (SEQ ID NO:4483) HIF-1α-3292 21 nt Targ: 5′-AGTTGAAAAATTTTTACACCT-3′ (SEQ ID NO:4484) HIF-1α-3310 21 nt Targ: 5′-CCTTTTTTTTCACATTTTACA-3′ (SEQ ID NO:4485) HIF-1α-3358 21 nt Targ: 5′-GTGGTAGCCACAATTGCACAA-3′ (SEQ ID NO:4486) HIF-1α-3360 21 nt Targ: 5′-GGTAGCCACAATTGCACAATA-3′ (SEQ ID NO:4487) HIF-1α-3362 21 nt Targ: 5′-TAGCCACAATTGCACAATATA-3′ (SEQ ID NO:4488) HIF-1α-3364 21 nt Targ: 5′-GCCACAATTGCACAATATATT-3′ (SEQ ID NO:4489) HIF-1α-3366 21 nt Targ: 5′-CACAATTGCACAATATATTTT-3′ (SEQ ID NO:4490) HIF-1α-3368 21 nt Targ: 5′-CAATTGCACAATATATTTTCT-3′ (SEQ ID NO:4491) HIF-1α-3374 21 nt Targ: 5′-CACAATATATTTTCTTAAAAA-3′ (SEQ ID NO:4492) HIF-1α-3425 21 nt Targ: 5′-GCGTTTATAAAACTAGTTTTT-3′ (SEQ ID NO:4493) HIF-1α-3426 21 nt Targ: 5′-CGTTTATAAAACTAGTTTTTA-3′ (SEQ ID NO:4494) HIF-1α-3428 21 nt Targ: 5′-TTTATAAAACTAGTTTTTAAG-3′ (SEQ ID NO:4495) HIF-1α-3430 21 nt Targ: 5′-TATAAAACTAGTTTTTAAGAA-3′ (SEQ ID NO:4496) HIF-1α-3442 21 nt Targ: 5′-TTTTAAGAAGAAATTTTTTTT-3′ (SEQ ID NO:4497) HIF-1α-3448 21 nt Targ: 5′-GAAGAAATTTTTTTTGGCCTA-3′ (SEQ ID NO:4498) HIF-1α-3450 21 nt Targ: 5′-AGAAATTTTTTTTGGCCTATG-3′ (SEQ ID NO:4499) HIF-1α-3465 21 nt Targ: 5′-CCTATGAAATTGTTAAACCTG-3′ (SEQ ID NO:4500) HIF-1α-3493 21 nt Targ: 5′-ACATTGTTAATCATATAATAA-3′ (SEQ ID NO:4501) HIF-1α-3529 21 nt Targ: 5′-GTATGGTTTATTATTTAAATG-3′ (SEQ ID NO:4502) HIF-1α-3546 21 nt Targ: 5′-AATGGGTAAAGCCATTTACAT-3′ (SEQ ID NO:4503) HIF-1α-3557 21 nt Targ: 5′-CCATTTACATAATATAGAAAG-3′ (SEQ ID NO:4504) HIF-1α-3592 21 nt Targ: 5′-AGAAGGTATGTGGCATTTATT-3′ (SEQ ID NO:4505) HIF-1α-3594 21 nt Targ: 5′-AAGGTATGTGGCATTTATTTG-3′ (SEQ ID NO:4506) HIF-1α-3596 21 nt Targ: 5′-GGTATGTGGCATTTATTTGGA-3′ (SEQ ID NO:4507) HIF-1α-3598 21 nt Targ: 5′-TATGTGGCATTTATTTGGATA-3′ (SEQ ID NO:4508) HIF-1α-3600 21 nt Targ: 5′-TGTGGCATTTATTTGGATAAA-3′ (SEQ ID NO:4509) HIF-1α-3602 21 nt Targ: 5′-TGGCATTTATTTGGATAAAAT-3′ (SEQ ID NO:4510) HIF-1α-3604 21 nt Targ: 5′-GCATTTATTTGGATAAAATTC-3′ (SEQ ID NO:4511) HIF-1α-3606 21 nt Targ: 5′-ATTTATTTGGATAAAATTCTC-3′ (SEQ ID NO:4512) HIF-1α-3608 21 nt Targ: 5′-TTATTTGGATAAAATTCTCAA-3′ (SEQ ID NO:4513) HIF-1α-3608 21 nt Targ: 5′-TTATTTGGATAAAATTCTCAA-3′ (SEQ ID NO:4514) HIF-1α-3610 21 nt Targ: 5′-ATTTGGATAAAATTCTCAATT-3′ (SEQ ID NO:4515) HIF-1α-3612 21 nt Targ: 5′-TTGGATAAAATTCTCAATTCA-3′ (SEQ ID NO:4516) HIF-1α-3614 21 nt Targ: 5′-GGATAAAATTCTCAATTCAGA-3′ (SEQ ID NO:4517) HIF-1α-3616 21 nt Targ: 5′-ATAAAATTCTCAATTCAGAGA-3′ (SEQ ID NO:4518) HIF-1α-3640 21 nt Targ: 5′-CATCTGATGTTTCTATAGTCA-3′ (SEQ ID NO:4519) HIF-1α-3646 21 nt Targ: 5′-ATGTTTCTATAGTCACTTTGC-3′ (SEQ ID NO:4520) HIF-1α-3651 21 nt Targ: 5′-TCTATAGTCACTTTGCCAGCT-3′ (SEQ ID NO:4521) HIF-1α-3670 21 nt Targ: 5′-CTCAAAAGAAAACAATACCCT-3′ (SEQ ID NO:4522) HIF-1α-3743 21 nt Targ: 5′-TGTTCTGCCTACCCTGTTGGT-3′ (SEQ ID NO:4523) HIF-1α-3745 21 nt Targ: 5′-TTCTGCCTACCCTGTTGGTAT-3′ (SEQ ID NO:4524) HIF-1α-3746 21 nt Targ: 5′-TCTGCCTACCCTGTTGGTATA-3′ (SEQ ID NO:4525) HIF-1α-3748 21 nt Targ: 5′-TGCCTACCCTGTTGGTATAAA-3′ (SEQ ID NO:4526) HIF-1α-3749 21 nt Targ: 5′-GCCTACCCTGTTGGTATAAAG-3′ (SEQ ID NO:4527) HIF-1α-3754 21 nt Targ: 5′-CCCTGTTGGTATAAAGATATT-3′ (SEQ ID NO:4528) HIF-1α-3757 21 nt Targ: 5′-TGTTGGTATAAAGATATTTTG-3′ (SEQ ID NO:4529) HIF-1α-3791 21 nt Targ: 5′-CAAGAAAAAAAAAATCATGCA-3′ (SEQ ID NO:4530) HIF-1α-3830 21 nt Targ: 5′-AGTATGTTAATTTGCTCAAAA-3′ (SEQ ID NO:4531) HIF-1α-3861 21 nt Targ: 5′-GATTTTATGCACTTTGTCGCT-3′ (SEQ ID NO:4532) HIF-1α-3863 21 nt Targ: 5′-TTTTATGCACTTTGTCGCTAT-3′ (SEQ ID NO:4533) HIF-1α-3865 21 nt Targ: 5′-TTATGCACTTTGTCGCTATTA-3′ (SEQ ID NO:4534) HIF-1α-3867 21 nt Targ: 5′-ATGCACTTTGTCGCTATTAAC-3′ (SEQ ID NO:4535) HIF-1α-3869 21 nt Targ: 5′-GCACTTTGTCGCTATTAACAT-3′ (SEQ ID NO:4536) HIF-1α-3871 21 nt Targ: 5′-ACTTTGTCGCTATTAACATCC-3′ (SEQ ID NO:4537) HIF-1α-3873 21 nt Targ: 5′-TTTGTCGCTATTAACATCCTT-3′ (SEQ ID NO:4538) HIF-1α-3875 21 nt Targ: 5′-TGTCGCTATTAACATCCTTTT-3′ (SEQ ID NO:4539) HIF-1α-3877 21 nt Targ: 5′-TCGCTATTAACATCCTTTTTT-3′ (SEQ ID NO:4540) HIF-1α-3880 21 nt Targ: 5′-CTATTAACATCCTTTTTTTCA-3′ (SEQ ID NO:4541) HIF-1α-3916 21 nt Targ: 5′-TTGAGTAATTTTAGAAGCATT-3′ (SEQ ID NO:4542) HIF-1α-3918 21 nt Targ: 5′-GAGTAATTTTAGAAGCATTAT-3′ (SEQ ID NO:4543) HIF-1α-3920 21 nt Targ: 5′-GTAATTTTAGAAGCATTATTT-3′ (SEQ ID NO:4544) HIF-1α-3922 21 nt Targ: 5′-AATTTTAGAAGCATTATTTTA-3′ (SEQ ID NO:4545) HIF-1α-3924 21 nt Targ: 5′-TTTTAGAAGCATTATTTTAGG-3′ (SEQ ID NO:4546) HIF-1α-3926 21 nt Targ: 5′-TTAGAAGCATTATTTTAGGAA-3′ (SEQ ID NO:4547) HIF-1α-3928 21 nt Targ: 5′-AGAAGCATTATTTTAGGAATA-3′ (SEQ ID NO:4548) HIF-1α-3930 21 nt Targ: 5′-AAGCATTATTTTAGGAATATA-3′ (SEQ ID NO:4549) HIF-1α-3961 21 nt Targ: 5′-AGTAAATATCTTGTTTTTTCT-3′ (SEQ ID NO:4550) HIF-1α-3980 21 nt Targ: 5′-CTATGTACATTGTACAAATTT-3′ (SEQ ID NO:4551) HIF-1α-3999 21 nt Targ: 5′-TTTTCATTCCTTTTGCTCTTT-3′ (SEQ ID NO:4552) HIF-1α-4000 21 nt Targ: 5′-TTTCATTCCTTTTGCTCTTTG-3′ (SEQ ID NO:4553) HIF-1α-4001 21 nt Targ: 5′-TTCATTCCTTTTGCTCTTTGT-3′ (SEQ ID NO:4554) HIF-1α-4003 21 nt Targ: 5′-CATTCCTTTTGCTCTTTGTGG-3′ (SEQ ID NO:4555) HIF-1α-4004 21 nt Targ: 5′-ATTCCTTTTGCTCTTTGTGGT-3′ (SEQ ID NO:4556) HIF-1α-4005 21 nt Targ: 5′-TTCCTTTTGCTCTTTGTGGTT-3′ (SEQ ID NO:4557) HIF-1α-4006 21 nt Targ: 5′-TCCTTTTGCTCTTTGTGGTTG-3′ (SEQ ID NO:4558) HIF-1α-4007 21 nt Targ: 5′-CCTTTTGCTCTTTGTGGTTGG-3′ (SEQ ID NO:4559) HIF-1α-4008 21 nt Targ: 5′-CTTTTGCTCTTTGTGGTTGGA-3′ (SEQ ID NO:4560) HIF-1α-4009 21 nt Targ: 5′-TTTTGCTCTTTGTGGTTGGAT-3′ (SEQ ID NO:4561) HIF-1α-4010 21 nt Targ: 5′-TTTGCTCTTTGTGGTTGGATC-3′ (SEQ ID NO:4562) HIF-1α-4012 21 nt Targ: 5′-TGCTCTTTGTGGTTGGATCTA-3′ (SEQ ID NO:4563) HIF-1α-4055 21 nt Targ: 5′-ACATCAAATAAACATCTTCTG-3′ (SEQ ID NO:4564) HIF-1α-4057 21 nt Targ: 5′-ATCAAATAAACATCTTCTGTG-3′ (SEQ ID NO:4565) HIF-1α-4059 21 nt Targ: 5′-CAAATAAACATCTTCTGTGGA-3′ (SEQ ID NO:4566) HIF-1α-4061 21 nt Targ: 5′-AATAAACATCTTCTGTGGACC-3′ (SEQ ID NO:4567) HIF-1α-4063 21 nt Targ: 5′-TAAACATCTTCTGTGGACCAG-3′ (SEQ ID NO:4568) HIF-1α-4065 21 nt Targ: 5′-AACATCTTCTGTGGACCAGGC-3′ (SEQ ID NO:4569) HIF-1α-m38 21 nt Targ: 5′-GCCCGCGGGCGCGCGCGTTGG-3′ (SEQ ID NO:4570) HIF-1α-m40 21 nt Targ: 5′-CCGCGGGCGCGCGCGTTGGGT-3′ (SEQ ID NO:4571) HIF-1α-m41 21 nt Targ: 5′-CGCGGGCGCGCGCGTTGGGTG-3′ (SEQ ID NO:4572) HIF-1α-m42 21 nt Targ: 5′-GCGGGCGCGCGCGTTGGGTGC-3′ (SEQ ID NO:4573) HIF-1α-m43 21 nt Targ: 5′-CGGGCGCGCGCGTTGGGTGCT-3′ (SEQ ID NO:4574) HIF-1α-m44 21 nt Targ: 5′-GGGCGCGCGCGTTGGGTGCTG-3′ (SEQ ID NO:4575) HIF-1α-m45 21 nt Targ: 5′-GGCGCGCGCGTTGGGTGCTGA-3′ (SEQ ID NO:4576) HIF-1α-m46 21 nt Targ: 5′-GCGCGCGCGTTGGGTGCTGAG-3′ (SEQ ID NO:4577) HIF-1α-m47 21 nt Targ: 5′-CGCGCGCGTTGGGTGCTGAGC-3′ (SEQ ID NO:4578) HIF-1α-m49 21 nt Targ: 5′-CGCGCGTTGGGTGCTGAGCGG-3′ (SEQ ID NO:4579) HIF-1α-m50 21 nt Targ: 5′-GCGCGTTGGGTGCTGAGCGGG-3′ (SEQ ID NO:4580) HIF-1α-m51 21 nt Targ: 5′-CGCGTTGGGTGCTGAGCGGGC-3′ (SEQ ID NO:4581) HIF-1α-m52 21 nt Targ: 5′-GCGTTGGGTGCTGAGCGGGCG-3′ (SEQ ID NO:4582) HIF-1α-m53 21 nt Targ: 5′-CGTTGGGTGCTGAGCGGGCGC-3′ (SEQ ID NO:4583) HIF-1α-m55 21 nt Targ: 5′-TTGGGTGCTGAGCGGGCGCGC-3′ (SEQ ID NO:4584) HIF-1α-m97 21 nt Targ: 5′-CCCTCGCCGCGCGCCCGAGCG-3′ (SEQ ID NO:4585) HIF-1α-m98 21 nt Targ: 5′-CCTCGCCGCGCGCCCGAGCGC-3′ (SEQ ID NO:4586) HIF-1α-m99 21 nt Targ: 5′-CTCGCCGCGCGCCCGAGCGCG-3′ (SEQ ID NO:4587) HIF-1α-m100 21 nt Targ: 5′-TCGCCGCGCGCCCGAGCGCGC-3′ (SEQ ID NO:4588) HIF-1α-m139 21 nt Targ: 5′-CCTGCCGCTGCTTCAGCGCCT-3′ (SEQ ID NO:4589) HIF-1α-m141 21 nt Targ: 5′-TGCCGCTGCTTCAGCGCCTCA-3′ (SEQ ID NO:4590) HIF-1α-m145 21 nt Targ: 5′-GCTGCTTCAGCGCCTCAGTGC-3′ (SEQ ID NO:4591) HIF-1α-m146 21 nt Targ: 5′-CTGCTTCAGCGCCTCAGTGCA-3′ (SEQ ID NO:4592) HIF-1α-m148 21 nt Targ: 5′-GCTTCAGCGCCTCAGTGCACA-3′ (SEQ ID NO:4593) HIF-1α-m152 21 nt Targ: 5′-CAGCGCCTCAGTGCACAGAGC-3′ (SEQ ID NO:4594) HIF-1α-m271 21 nt Targ: 5′-GAGCCGGAGCTCAGCGAGCGC-3′ (SEQ ID NO:4595) HIF-1α-m277 21 nt Targ: 5′-GAGCTCAGCGAGCGCAGCCTG-3′ (SEQ ID NO:4596) HIF-1α-m282 21 nt Targ: 5′-CAGCGAGCGCAGCCTGCAGCT-3′ (SEQ ID NO:4597) HIF-1α-m283 21 nt Targ: 5′-AGCGAGCGCAGCCTGCAGCTC-3′ (SEQ ID NO:4598) HIF-1α-m284 21 nt Targ: 5′-GCGAGCGCAGCCTGCAGCTCC-3′ (SEQ ID NO:4599) HIF-1α-m286 21 nt Targ: 5′-GAGCGCAGCCTGCAGCTCCCG-3′ (SEQ ID NO:4600) HIF-1α-m289 21 nt Targ: 5′-CGCAGCCTGCAGCTCCCGCCT-3′ (SEQ ID NO:4601) HIF-1α-m348 21 nt Targ: 5′-TGGACTTGTCTCTTTCTCCGC-3′ (SEQ ID NO:4602) HIF-1α-m350 21 nt Targ: 5′-GACTTGTCTCTTTCTCCGCGC-3′ (SEQ ID NO:4603) HIF-1α-m352 21 nt Targ: 5′-CTTGTCTCTTTCTCCGCGCGC-3′ (SEQ ID NO:4604) HIF-1α-m353 21 nt Targ: 5′-TTGTCTCTTTCTCCGCGCGCG-3′ (SEQ ID NO:4605) HIF-1α-m354 21 nt Targ: 5′-TGTCTCTTTCTCCGCGCGCGC-3′ (SEQ ID NO:4606) HIF-1α-m357 21 nt Targ: 5′-CTCTTTCTCCGCGCGCGCGGA-3′ (SEQ ID NO:4607) HIF-1α-m359 21 nt Targ: 5′-CTTTCTCCGCGCGCGCGGACA-3′ (SEQ ID NO:4608) HIF-1α-m365 21 nt Targ: 5′-CCGCGCGCGCGGACAGAGCCG-3′ (SEQ ID NO:4609) HIF-1α-m597 21 nt Targ: 5′-GTGAGCTCACATCTTGATAAA-3′ (SEQ ID NO:4610) HIF-1α-m600 21 nt Targ: 5′-AGCTCACATCTTGATAAAGCT-3′ (SEQ ID NO:4611) HIF-1α-m712 21 nt Targ: 5′-TGGACTGTTTTTATCTGAAAG-3′ (SEQ ID NO:4612) HIF-1α-m1093 21 nt Targ: 5′-CACCCATGACGTGCTTGGTGC-3′ (SEQ ID NO:4613) HIF-1α-m1593 21 nt Targ: 5′-GATACAAGCTGCCTTTTTGAT-3′ (SEQ ID NO:4614) HIF-1α-m1595 21 nt Targ: 5′-TACAAGCTGCCTTTTTGATAA-3′ (SEQ ID NO:4615) HIF-1α-m1596 21 nt Targ: 5′-ACAAGCTGCCTTTTTGATAAG-3′ (SEQ ID NO:4616) HIF-1α-m1599 21 nt Targ: 5′-AGCTGCCTTTTTGATAAGCTT-3′ (SEQ ID NO:4617) HIF-1α-m1632 21 nt Targ: 5′-GATGCTCTCACTCTGCTGGCT-3′ (SEQ ID NO:4618) HIF-1α-m1633 21 nt Targ: 5′-ATGCTCTCACTCTGCTGGCTC-3′ (SEQ ID NO:4619) HIF-1α-m1634 21 nt Targ: 5′-TGCTCTCACTCTGCTGGCTCC-3′ (SEQ ID NO:4620) HIF-1α-m1642 21 nt Targ: 5′-CTCTGCTGGCTCCAGCTGCCG-3′ (SEQ ID NO:4621) HIF-1α-m1830 21 nt Targ: 5′-CTTCGAAGTAGTGCTGATCCT-3′ (SEQ ID NO:4622) HIF-1α-m2041 21 nt Targ: 5′-AATATTGCTTTGATGTGGATA-3′ (SEQ ID NO:4623) HIF-1α-m2043 21 nt Targ: 5′-TATTGCTTTGATGTGGATAGC-3′ (SEQ ID NO:4624) HIF-1α-m2045 21 nt Targ: 5′-TTGCTTTGATGTGGATAGCGA-3′ (SEQ ID NO:4625) HIF-1α-m2650 21 nt Targ: 5′-ATGATGGCTCCCTTTTTCAAG-3′ (SEQ ID NO:4626) HIF-1α-m3030 21 nt Targ: 5′-GTTTCTGTTGGTTATTTTTGG-3′ (SEQ ID NO:4627) HIF-1α-m3557 21 nt Targ: 5′-TGTTAAGCCTGGATCATGAAG-3′ (SEQ ID NO:4628) HIF-1α-m3562 21 nt Targ: 5′-AGCCTGGATCATGAAGCTGTT-3′ (SEQ ID NO:4629) HIF-1α-m3576 21 nt Targ: 5′-AGCTGTTGATCTTATAATGAT-3′ (SEQ ID NO:4630) HIF-1α-m3592 21 nt Targ: 5′-ATGATTCTTAAACTGTATGGT-3′ (SEQ ID NO:4631) HIF-1α-m3604 21 nt Targ: 5′-CTGTATGGTTTCTTTATATGG-3′ (SEQ ID NO:4632) HIF-1α-m4023 21 nt Targ: 5′-CATAGTAAACATCTTGTTTTT-3′ (SEQ ID NO:4633) HIF-1α-m4064 21 nt Targ: 5′-TTTTCGTTCCCTTGCTCTTTG-3′ (SEQ ID NO:4634) HIF-1α-m4065 21 nt Targ: 5′-TTTCGTTCCCTTGCTCTTTGT-3′ (SEQ ID NO:4635) HIF-1α-m4070 21 nt Targ: 5′-TTCCCTTGCTCTTTGTGGTTG-3′ (SEQ ID NO:4636) HIF-1α-m4549 21 nt Targ: 5′-TTTCCGCGCTCTCAGGGAGCT-3′ (SEQ ID NO:4637) HIF-1α-m4691 21 nt Targ: 5′-ACCTGATGTTTCTTTACTTTG-3′ (SEQ ID NO:4638) HIF-1α-m4692 21 nt Targ: 5′-CCTGATGTTTCTTTACTTTGC-3′ (SEQ ID NO:4639) HIF-1α-m4693 21 nt Targ: 5′-CTGATGTTTCTTTACTTTGCC-3′ (SEQ ID NO:4640) HIF-1α-m4709 21 nt Targ: 5′-TTGCCAGCTTTAAAAAAGTAT-3′ (SEQ ID NO:4641) HIF-1α-463 21 nt Targ: 5′-AAAGATAAGTTCTGAACGTCG-3′ (SEQ ID NO:4642) HIF-1α-466 21 nt Targ: 5′-GATAAGTTCTGAACGTCGAAA-3′ (SEQ ID NO:4643) HIF-1α-468 21 nt Targ: 5′-TAAGTTCTGAACGTCGAAAAG-3′ (SEQ ID NO:4644) HIF-1α-472 21 nt Targ: 5′-TTCTGAACGTCGAAAAGAAAA-3′ (SEQ ID NO:4645) HIF-1α-480 21 nt Targ: 5′-GTCGAAAAGAAAAGTCTCGAG-3′ (SEQ ID NO:4646) HIF-1α-481 21 nt Targ: 5′-TCGAAAAGAAAAGTCTCGAGA-3′ (SEQ ID NO:4647) HIF-1α-516 21 nt Targ: 5′-GGCGAAGTAAAGAATCTGAAG-3′ (SEQ ID NO:4648) HIF-1α-517 21 nt Targ: 5′-GCGAAGTAAAGAATCTGAAGT-3′ (SEQ ID NO:4649) HIF-1α-519 21 nt Targ: 5′-GAAGTAAAGAATCTGAAGTTT-3′ (SEQ ID NO:4650) HIF-1α-520 21 nt Targ: 5′-AAGTAAAGAATCTGAAGTTTT-3′ (SEQ ID NO:4651) HIF-1α-522 21 nt Targ: 5′-GTAAAGAATCTGAAGTTTTTT-3′ (SEQ ID NO:4652) HIF-1α-529 21 nt Targ: 5′-ATCTGAAGTTTTTTATGAGCT-3′ (SEQ ID NO:4653) HIF-1α-557 21 nt Targ: 5′-CAGTTGCCACTTCCACATAAT-3′ (SEQ ID NO:4654) HIF-1α-576 21 nt Targ: 5′-ATGTGAGTTCGCATCTTGATA-3′ (SEQ ID NO:4655) HIF-1α-608 21 nt Targ: 5′-ATGAGGCTTACCATCAGCTAT-3′ (SEQ ID NO:4656) HIF-1α-636 21 nt Targ: 5′-TGAGGAAACTTCTGGATGCTG-3′ (SEQ ID NO:4657) HIF-1α-652 21 nt Targ: 5′-TGCTGGTGATTTGGATATTGA-3′ (SEQ ID NO:4658) HIF-1α-654 21 nt Targ: 5′-CTGGTGATTTGGATATTGAAG-3′ (SEQ ID NO:4659) HIF-1α-660 21 nt Targ: 5′-ATTTGGATATTGAAGATGACA-3′ (SEQ ID NO:4660) HIF-1α-661 21 nt Targ: 5′-TTTGGATATTGAAGATGACAT-3′ (SEQ ID NO:4661) HIF-1α-663 21 nt Targ: 5′-TGGATATTGAAGATGACATGA-3′ (SEQ ID NO:4662) HIF-1α-664 21 nt Targ: 5′-GGATATTGAAGATGACATGAA-3′ (SEQ ID NO:4663) HIF-1α-671 21 nt Targ: 5′-GAAGATGACATGAAAGCACAG-3′ (SEQ ID NO:4664) HIF-1α-672 21 nt Targ: 5′-AAGATGACATGAAAGCACAGA-3′ (SEQ ID NO:4665) HIF-1α-681 21 nt Targ: 5′-TGAAAGCACAGATGAATTGCT-3′ (SEQ ID NO:4666) HIF-1α-687 21 nt Targ: 5′-CACAGATGAATTGCTTTTATT-3′ (SEQ ID NO:4667) HIF-1α-688 21 nt Targ: 5′-ACAGATGAATTGCTTTTATTT-3′ (SEQ ID NO:4668) HIF-1α-701 21 nt Targ: 5′-TTTTATTTGAAAGCCTTGGAT-3′ (SEQ ID NO:4669) HIF-1α-702 21 nt Targ: 5′-TTTATTTGAAAGCCTTGGATG-3′ (SEQ ID NO:4670) HIF-1α-708 21 nt Targ: 5′-TGAAAGCCTTGGATGGTTTTG-3′ (SEQ ID NO:4671) HIF-1α-723 21 nt Targ: 5′-GTTTTGTTATGGTTCTCACAG-3′ (SEQ ID NO:4672) HIF-1α-729 21 nt Targ: 5′-TTATGGTTCTCACAGATGATG-3′ (SEQ ID NO:4673) HIF-1α-730 21 nt Targ: 5′-TATGGTTCTCACAGATGATGG-3′ (SEQ ID NO:4674) HIF-1α-739 21 nt Targ: 5′-CACAGATGATGGTGACATGAT-3′ (SEQ ID NO:4675) HIF-1α-744 21 nt Targ: 5′-ATGATGGTGACATGATTTACA-3′ (SEQ ID NO:4676) HIF-1α-745 21 nt Targ: 5′-TGATGGTGACATGATTTACAT-3′ (SEQ ID NO:4677) HIF-1α-753 21 nt Targ: 5′-ACATGATTTACATTTCTGATA-3′ (SEQ ID NO:4678) HIF-1α-755 21 nt Targ: 5′-ATGATTTACATTTCTGATAAT-3′ (SEQ ID NO:4679) HIF-1α-757 21 nt Targ: 5′-GATTTACATTTCTGATAATGT-3′ (SEQ ID NO:4680) HIF-1α-762 21 nt Targ: 5′-ACATTTCTGATAATGTGAACA-3′ (SEQ ID NO:4681) HIF-1α-770 21 nt Targ: 5′-GATAATGTGAACAAATACATG-3′ (SEQ ID NO:4682) HIF-1α-771 21 nt Targ: 5′-ATAATGTGAACAAATACATGG-3′ (SEQ ID NO:4683) HIF-1α-772 21 nt Targ: 5′-TAATGTGAACAAATACATGGG-3′ (SEQ ID NO:4684) HIF-1α-773 21 nt Targ: 5′-AATGTGAACAAATACATGGGA-3′ (SEQ ID NO:4685) HIF-1α-774 21 nt Targ: 5′-ATGTGAACAAATACATGGGAT-3′ (SEQ ID NO:4686) HIF-1α-775 21 nt Targ: 5′-TGTGAACAAATACATGGGATT-3′ (SEQ ID NO:4687) HIF-1α-785 21 nt Targ: 5′-TACATGGGATTAACTCAGTTT-3′ (SEQ ID NO:4688) HIF-1α-786 21 nt Targ: 5′-ACATGGGATTAACTCAGTTTG-3′ (SEQ ID NO:4689) HIF-1α-801 21 nt Targ: 5′-AGTTTGAACTAACTGGACACA-3′ (SEQ ID NO:4690) HIF-1α-811 21 nt Targ: 5′-AACTGGACACAGTGTGTTTGA-3′ (SEQ ID NO:4691) HIF-1α-812 21 nt Targ: 5′-ACTGGACACAGTGTGTTTGAT-3′ (SEQ ID NO:4692) HIF-1α-825 21 nt Targ: 5′-TGTTTGATTTTACTCATCCAT-3′ (SEQ ID NO:4693) HIF-1α-827 21 nt Targ: 5′-TTTGATTTTACTCATCCATGT-3′ (SEQ ID NO:4694) HIF-1α-841 21 nt Targ: 5′-TCCATGTGACCATGAGGAAAT-3′ (SEQ ID NO:4695) HIF-1α-843 21 nt Targ: 5′-CATGTGACCATGAGGAAATGA-3′ (SEQ ID NO:4696) HIF-1α-849 21 nt Targ: 5′-ACCATGAGGAAATGAGAGAAA-3′ (SEQ ID NO:4697) HIF-1α-861 21 nt Targ: 5′-TGAGAGAAATGCTTACACACA-3′ (SEQ ID NO:4698) HIF-1α-865 21 nt Targ: 5′-AGAAATGCTTACACACAGAAA-3′ (SEQ ID NO:4699) HIF-1α-866 21 nt Targ: 5′-GAAATGCTTACACACAGAAAT-3′ (SEQ ID NO:4700) HIF-1α-880 21 nt Targ: 5′-CAGAAATGGCCTTGTGAAAAA-3′ (SEQ ID NO:4701) HIF-1α-881 21 nt Targ: 5′-AGAAATGGCCTTGTGAAAAAG-3′ (SEQ ID NO:4702) HIF-1α-882 21 nt Targ: 5′-GAAATGGCCTTGTGAAAAAGG-3′ (SEQ ID NO:4703) HIF-1α-883 21 nt Targ: 5′-AAATGGCCTTGTGAAAAAGGG-3′ (SEQ ID NO:4704) HIF-1α-888 21 nt Targ: 5′-GCCTTGTGAAAAAGGGTAAAG-3′ (SEQ ID NO:4705) HIF-1α-904 21 nt Targ: 5′-TAAAGAACAAAACACACAGCG-3′ (SEQ ID NO:4706) HIF-1α-926 21 nt Targ: 5′-AGCTTTTTTCTCAGAATGAAG-3′ (SEQ ID NO:4707) HIF-1α-928 21 nt Targ: 5′-CTTTTTTCTCAGAATGAAGTG-3′ (SEQ ID NO:4708) HIF-1α-938 21 nt Targ: 5′-AGAATGAAGTGTACCCTAACT-3′ (SEQ ID NO:4709) HIF-1α-962 21 nt Targ: 5′-CGAGGAAGAACTATGAACATA-3′ (SEQ ID NO:4710) HIF-1α-963 21 nt Targ: 5′-GAGGAAGAACTATGAACATAA-3′ (SEQ ID NO:4711) HIF-1α-964 21 nt Targ: 5′-AGGAAGAACTATGAACATAAA-3′ (SEQ ID NO:4712) HIF-1α-1012 21 nt Targ: 5′-CACAGGCCACATTCACGTATA-3′ (SEQ ID NO:4713) HIF-1α-1058 21 nt Targ: 5′-TGTGGGTATAAGAAACCACCT-3′ (SEQ ID NO:4714) HIF-1α-1059 21 nt Targ: 5′-GTGGGTATAAGAAACCACCTA-3′ (SEQ ID NO:4715) HIF-1α-1123 21 nt Targ: 5′-AAATATTGAAATTCCTTTAGA-3′ (SEQ ID NO:4716) HIF-1α-1129 21 nt Targ: 5′-TGAAATTCCTTTAGATAGCAA-3′ (SEQ ID NO:4717) HIF-1α-1173 21 nt Targ: 5′-TGGATATGAAATTTTCTTATT-3′ (SEQ ID NO:4718) HIF-1α-1176 21 nt Targ: 5′-ATATGAAATTTTCTTATTGTG-3′ (SEQ ID NO:4719) HIF-1α-1177 21 nt Targ: 5′-TATGAAATTTTCTTATTGTGA-3′ (SEQ ID NO:4720) HIF-1α-1178 21 nt Targ: 5′-ATGAAATTTTCTTATTGTGAT-3′ (SEQ ID NO:4721) HIF-1α-1180 21 nt Targ: 5′-GAAATTTTCTTATTGTGATGA-3′ (SEQ ID NO:4722) HIF-1α-1181 21 nt Targ: 5′-AAATTTTCTTATTGTGATGAA-3′ (SEQ ID NO:4723) HIF-1α-1182 21 nt Targ: 5′-AATTTTCTTATTGTGATGAAA-3′ (SEQ ID NO:4724) HIF-1α-1186 21 nt Targ: 5′-TTCTTATTGTGATGAAAGAAT-3′ (SEQ ID NO:4725) HIF-1α-1191 21 nt Targ: 5′-ATTGTGATGAAAGAATTACCG-3′ (SEQ ID NO:4726) HIF-1α-1193 21 nt Targ: 5′-TGTGATGAAAGAATTACCGAA-3′ (SEQ ID NO:4727) HIF-1α-1198 21 nt Targ: 5′-TGAAAGAATTACCGAATTGAT-3′ (SEQ ID NO:4728) HIF-1α-1199 21 nt Targ: 5′-GAAAGAATTACCGAATTGATG-3′ (SEQ ID NO:4729) HIF-1α-1200 21 nt Targ: 5′-AAAGAATTACCGAATTGATGG-3′ (SEQ ID NO:4730) HIF-1α-1201 21 nt Targ: 5′-AAGAATTACCGAATTGATGGG-3′ (SEQ ID NO:4731) HIF-1α-1215 21 nt Targ: 5′-TGATGGGATATGAGCCAGAAG-3′ (SEQ ID NO:4732) HIF-1α-1222 21 nt Targ: 5′-ATATGAGCCAGAAGAACTTTT-3′ (SEQ ID NO:4733) HIF-1α-1240 21 nt Targ: 5′-TTTAGGCCGCTCAATTTATGA-3′ (SEQ ID NO:4734) HIF-1α-1254 21 nt Targ: 5′-TTTATGAATATTATCATGCTT-3′ (SEQ ID NO:4735) HIF-1α-1256 21 nt Targ: 5′-TATGAATATTATCATGCTTTG-3′ (SEQ ID NO:4736) HIF-1α-1287 21 nt Targ: 5′-ATCTGACCAAAACTCATCATG-3′ (SEQ ID NO:4737) HIF-1α-1292 21 nt Targ: 5′-ACCAAAACTCATCATGATATG-3′ (SEQ ID NO:4738) HIF-1α-1293 21 nt Targ: 5′-CCAAAACTCATCATGATATGT-3′ (SEQ ID NO:4739) HIF-1α-1302 21 nt Targ: 5′-ATCATGATATGTTTACTAAAG-3′ (SEQ ID NO:4740) HIF-1α-1306 21 nt Targ: 5′-TGATATGTTTACTAAAGGACA-3′ (SEQ ID NO:4741) HIF-1α-1362 21 nt Targ: 5′-GAGGTGGATATGTCTGGGTTG-3′ (SEQ ID NO:4742) HIF-1α-1376 21 nt Targ: 5′-TGGGTTGAAACTCAAGCAACT-3′ (SEQ ID NO:4743) HIF-1α-1393 21 nt Targ: 5′-AACTGTCATATATAACACCAA-3′ (SEQ ID NO:4744) HIF-1α-1409 21 nt Targ: 5′-ACCAAGAATTCTCAACCACAG-3′ (SEQ ID NO:4745) HIF-1α-1425 21 nt Targ: 5′-CACAGTGCATTGTATGTGTGA-3′ (SEQ ID NO:4746) HIF-1α-1426 21 nt Targ: 5′-ACAGTGCATTGTATGTGTGAA-3′ (SEQ ID NO:4747) HIF-1α-1438 21 nt Targ: 5′-ATGTGTGAATTACGTTGTGAG-3′ (SEQ ID NO:4748) HIF-1α-1439 21 nt Targ: 5′-TGTGTGAATTACGTTGTGAGT-3′ (SEQ ID NO:4749) HIF-1α-1440 21 nt Targ: 5′-GTGTGAATTACGTTGTGAGTG-3′ (SEQ ID NO:4750) HIF-1α-1441 21 nt Targ: 5′-TGTGAATTACGTTGTGAGTGG-3′ (SEQ ID NO:4751) HIF-1α-1459 21 nt Targ: 5′-TGGTATTATTCAGCACGACTT-3′ (SEQ ID NO:4752) HIF-1α-1477 21 nt Targ: 5′-CTTGATTTTCTCCCTTCAACA-3′ (SEQ ID NO:4753) HIF-1α-1494 21 nt Targ: 5′-AACAAACAGAATGTGTCCTTA-3′ (SEQ ID NO:4754) HIF-1α-1503 21 nt Targ: 5′-AATGTGTCCTTAAACCGGTTG-3′ (SEQ ID NO:4755) HIF-1α-1516 21 nt Targ: 5′-ACCGGTTGAATCTTCAGATAT-3′ (SEQ ID NO:4756) HIF-1α-1517 21 nt Targ: 5′-CCGGTTGAATCTTCAGATATG-3′ (SEQ ID NO:4757) HIF-1α-1518 21 nt Targ: 5′-CGGTTGAATCTTCAGATATGA-3′ (SEQ ID NO:4758) HIF-1α-1520 21 nt Targ: 5′-GTTGAATCTTCAGATATGAAA-3′ (SEQ ID NO:4759) HIF-1α-1521 21 nt Targ: 5′-TTGAATCTTCAGATATGAAAA-3′ (SEQ ID NO:4760) HIF-1α-1531 21 nt Targ: 5′-AGATATGAAAATGACTCAGCT-3′ (SEQ ID NO:4761) HIF-1α-1532 21 nt Targ: 5′-GATATGAAAATGACTCAGCTA-3′ (SEQ ID NO:4762) HIF-1α-1559 21 nt Targ: 5′-AAAGTTGAATCAGAAGATACA-3′ (SEQ ID NO:4763) HIF-1α-1561 21 nt Targ: 5′-AGTTGAATCAGAAGATACAAG-3′ (SEQ ID NO:4764) HIF-1α-1569 21 nt Targ: 5′-CAGAAGATACAAGTAGCCTCT-3′ (SEQ ID NO:4765) HIF-1α-1570 21 nt Targ: 5′-AGAAGATACAAGTAGCCTCTT-3′ (SEQ ID NO:4766) HIF-1α-1571 21 nt Targ: 5′-GAAGATACAAGTAGCCTCTTT-3′ (SEQ ID NO:4767) HIF-1α-1586 21 nt Targ: 5′-CTCTTTGACAAACTTAAGAAG-3′ (SEQ ID NO:4768) HIF-1α-1587 21 nt Targ: 5′-TCTTTGACAAACTTAAGAAGG-3′ (SEQ ID NO:4769) HIF-1α-1609 21 nt Targ: 5′-ACCTGATGCTTTAACTTTGCT-3′ (SEQ ID NO:4770) HIF-1α-1641 21 nt Targ: 5′-CTGGAGACACAATCATATCTT-3′ (SEQ ID NO:4771) HIF-1α-1642 21 nt Targ: 5′-TGGAGACACAATCATATCTTT-3′ (SEQ ID NO:4772) HIF-1α-1701 21 nt Targ: 5′-AACTTGAGGAAGTACCATTAT-3′ (SEQ ID NO:4773) HIF-1α-1702 21 nt Targ: 5′-ACTTGAGGAAGTACCATTATA-3′ (SEQ ID NO:4774) HIF-1α-1704 21 nt Targ: 5′-TTGAGGAAGTACCATTATATA-3′ (SEQ ID NO:4775) HIF-1α-1705 21 nt Targ: 5′-TGAGGAAGTACCATTATATAA-3′ (SEQ ID NO:4776) HIF-1α-1707 21 nt Targ: 5′-AGGAAGTACCATTATATAATG-3′ (SEQ ID NO:4777) HIF-1α-1708 21 nt Targ: 5′-GGAAGTACCATTATATAATGA-3′ (SEQ ID NO:4778) HIF-1α-1748 21 nt Targ: 5′-AACGAAAAATTACAGAATATA-3′ (SEQ ID NO:4779) HIF-1α-1749 21 nt Targ: 5′-ACGAAAAATTACAGAATATAA-3′ (SEQ ID NO:4780) HIF-1α-1752 21 nt Targ: 5′-AAAAATTACAGAATATAAATT-3′ (SEQ ID NO:4781) HIF-1α-1758 21 nt Targ: 5′-TACAGAATATAAATTTGGCAA-3′ (SEQ ID NO:4782) HIF-1α-1759 21 nt Targ: 5′-ACAGAATATAAATTTGGCAAT-3′ (SEQ ID NO:4783) HIF-1α-1842 21 nt Targ: 5′-ATCAAGAAGTTGCATTAAAAT-3′ (SEQ ID NO:4784) HIF-1α-1843 21 nt Targ: 5′-TCAAGAAGTTGCATTAAAATT-3′ (SEQ ID NO:4785) HIF-1α-1857 21 nt Targ: 5′-TAAAATTAGAACCAAATCCAG-3′ (SEQ ID NO:4786) HIF-1α-1858 21 nt Targ: 5′-AAAATTAGAACCAAATCCAGA-3′ (SEQ ID NO:4787) HIF-1α-1874 21 nt Targ: 5′-CCAGAGTCACTGGAACTTTCT-3′ (SEQ ID NO:4788) HIF-1α-1875 21 nt Targ: 5′-CAGAGTCACTGGAACTTTCTT-3′ (SEQ ID NO:4789) HIF-1α-1881 21 nt Targ: 5′-CACTGGAACTTTCTTTTACCA-3′ (SEQ ID NO:4790) HIF-1α-1966 21 nt Targ: 5′-GCCTAATAGTCCCAGTGAATA-3′ (SEQ ID NO:4791) HIF-1α-1967 21 nt Targ: 5′-CCTAATAGTCCCAGTGAATAT-3′ (SEQ ID NO:4792) HIF-1α-1968 21 nt Targ: 5′-CTAATAGTCCCAGTGAATATT-3′ (SEQ ID NO:4793) HIF-1α-1969 21 nt Targ: 5′-TAATAGTCCCAGTGAATATTG-3′ (SEQ ID NO:4794) HIF-1α-1970 21 nt Targ: 5′-AATAGTCCCAGTGAATATTGT-3′ (SEQ ID NO:4795) HIF-1α-1978 21 nt Targ: 5′-CAGTGAATATTGTTTTTATGT-3′ (SEQ ID NO:4796) HIF-1α-1979 21 nt Targ: 5′-AGTGAATATTGTTTTTATGTG-3′ (SEQ ID NO:4797) HIF-1α-1981 21 nt Targ: 5′-TGAATATTGTTTTTATGTGGA-3′ (SEQ ID NO:4798) HIF-1α-1983 21 nt Targ: 5′-AATATTGTTTTTATGTGGATA-3′ (SEQ ID NO:4799) HIF-1α-1984 21 nt Targ: 5′-ATATTGTTTTTATGTGGATAG-3′ (SEQ ID NO:4800) HIF-1α-1986 21 nt Targ: 5′-ATTGTTTTTATGTGGATAGTG-3′ (SEQ ID NO:4801) HIF-1α-1989 21 nt Targ: 5′-GTTTTTATGTGGATAGTGATA-3′ (SEQ ID NO:4802) HIF-1α-1996 21 nt Targ: 5′-TGTGGATAGTGATATGGTCAA-3′ (SEQ ID NO:4803) HIF-1α-1998 21 nt Targ: 5′-TGGATAGTGATATGGTCAATG-3′ (SEQ ID NO:4804) HIF-1α-1999 21 nt Targ: 5′-GGATAGTGATATGGTCAATGA-3′ (SEQ ID NO:4805) HIF-1α-2000 21 nt Targ: 5′-GATAGTGATATGGTCAATGAA-3′ (SEQ ID NO:4806) HIF-1α-2004 21 nt Targ: 5′-GTGATATGGTCAATGAATTCA-3′ (SEQ ID NO:4807) HIF-1α-2007 21 nt Targ: 5′-ATATGGTCAATGAATTCAAGT-3′ (SEQ ID NO:4808) HIF-1α-2008 21 nt Targ: 5′-TATGGTCAATGAATTCAAGTT-3′ (SEQ ID NO:4809) HIF-1α-2013 21 nt Targ: 5′-TCAATGAATTCAAGTTGGAAT-3′ (SEQ ID NO:4810) HIF-1α-2014 21 nt Targ: 5′-CAATGAATTCAAGTTGGAATT-3′ (SEQ ID NO:4811) HIF-1α-2016 21 nt Targ: 5′-ATGAATTCAAGTTGGAATTGG-3′ (SEQ ID NO:4812) HIF-1α-2022 21 nt Targ: 5′-TCAAGTTGGAATTGGTAGAAA-3′ (SEQ ID NO:4813) HIF-1α-2028 21 nt Targ: 5′-TGGAATTGGTAGAAAAACTTT-3′ (SEQ ID NO:4814) HIF-1α-2029 21 nt Targ: 5′-GGAATTGGTAGAAAAACTTTT-3′ (SEQ ID NO:4815) HIF-1α-2035 21 nt Targ: 5′-GGTAGAAAAACTTTTTGCTGA-3′ (SEQ ID NO:4816) HIF-1α-2036 21 nt Targ: 5′-GTAGAAAAACTTTTTGCTGAA-3′ (SEQ ID NO:4817) HIF-1α-2043 21 nt Targ: 5′-AACTTTTTGCTGAAGACACAG-3′ (SEQ ID NO:4818) HIF-1α-2050 21 nt Targ: 5′-TGCTGAAGACACAGAAGCAAA-3′ (SEQ ID NO:4819) HIF-1α-2051 21 nt Targ: 5′-GCTGAAGACACAGAAGCAAAG-3′ (SEQ ID NO:4820) HIF-1α-2059 21 nt Targ: 5′-CACAGAAGCAAAGAACCCATT-3′ (SEQ ID NO:4821) HIF-1α-2068 21 nt Targ: 5′-AAAGAACCCATTTTCTACTCA-3′ (SEQ ID NO:4822) HIF-1α-2085 21 nt Targ: 5′-CTCAGGACACAGATTTAGACT-3′ (SEQ ID NO:4823) HIF-1α-2092 21 nt Targ: 5′-CACAGATTTAGACTTGGAGAT-3′ (SEQ ID NO:4824) HIF-1α-2094 21 nt Targ: 5′-CAGATTTAGACTTGGAGATGT-3′ (SEQ ID NO:4825) HIF-1α-2095 21 nt Targ: 5′-AGATTTAGACTTGGAGATGTT-3′ (SEQ ID NO:4826) HIF-1α-2105 21 nt Targ: 5′-TTGGAGATGTTAGCTCCCTAT-3′ (SEQ ID NO:4827) HIF-1α-2134 21 nt Targ: 5′-GGATGATGACTTCCAGTTACG-3′ (SEQ ID NO:4828) HIF-1α-2159 21 nt Targ: 5′-TTCGATCAGTTGTCACCATTA-3′ (SEQ ID NO:4829) HIF-1α-2166 21 nt Targ: 5′-AGTTGTCACCATTAGAAAGCA-3′ (SEQ ID NO:4830) HIF-1α-2221 21 nt Targ: 5′-CACAGTTACAGTATTCCAGCA-3′ (SEQ ID NO:4831) HIF-1α-2295 21 nt Targ: 5′-ATGAATTAAAAACAGTGACAA-3′ (SEQ ID NO:4832) HIF-1α-2296 21 nt Targ: 5′-TGAATTAAAAACAGTGACAAA-3′ (SEQ ID NO:4833) HIF-1α-2297 21 nt Targ: 5′-GAATTAAAAACAGTGACAAAA-3′ (SEQ ID NO:4834) HIF-1α-2305 21 nt Targ: 5′-AACAGTGACAAAAGACCGTAT-3′ (SEQ ID NO:4835) HIF-1α-2307 21 nt Targ: 5′-CAGTGACAAAAGACCGTATGG-3′ (SEQ ID NO:4836) HIF-1α-2319 21 nt Targ: 5′-ACCGTATGGAAGACATTAAAA-3′ (SEQ ID NO:4837) HIF-1α-2322 21 nt Targ: 5′-GTATGGAAGACATTAAAATAT-3′ (SEQ ID NO:4838) HIF-1α-2323 21 nt Targ: 5′-TATGGAAGACATTAAAATATT-3′ (SEQ ID NO:4839) HIF-1α-2325 21 nt Targ: 5′-TGGAAGACATTAAAATATTGA-3′ (SEQ ID NO:4840) HIF-1α-2404 21 nt Targ: 5′-ATATAGAGATACTCAAAGTCG-3′ (SEQ ID NO:4841) HIF-1α-2446 21 nt Targ: 5′-AGGAAAAGGAGTCATAGAACA-3′ (SEQ ID NO:4842) HIF-1α-2450 21 nt Targ: 5′-AAAGGAGTCATAGAACAGACA-3′ (SEQ ID NO:4843) HIF-1α-2451 21 nt Targ: 5′-AAGGAGTCATAGAACAGACAG-3′ (SEQ ID NO:4844) HIF-1α-2467 21 nt Targ: 5′-GACAGAAAAATCTCATCCAAG-3′ (SEQ ID NO:4845) HIF-1α-2468 21 nt Targ: 5′-ACAGAAAAATCTCATCCAAGA-3′ (SEQ ID NO:4846) HIF-1α-2495 21 nt Targ: 5′-AACGTGTTATCTGTCGCTTTG-3′ (SEQ ID NO:4847) HIF-1α-2496 21 nt Targ: 5′-ACGTGTTATCTGTCGCTTTGA-3′ (SEQ ID NO:4848) HIF-1α-2503 21 nt Targ: 5′-ATCTGTCGCTTTGAGTCAAAG-3′ (SEQ ID NO:4849) HIF-1α-2510 21 nt Targ: 5′-GCTTTGAGTCAAAGAACTACA-3′ (SEQ ID NO:4850) HIF-1α-2511 21 nt Targ: 5′-CTTTGAGTCAAAGAACTACAG-3′ (SEQ ID NO:4851) HIF-1α-2517 21 nt Targ: 5′-GTCAAAGAACTACAGTTCCTG-3′ (SEQ ID NO:4852) HIF-1α-2518 21 nt Targ: 5′-TCAAAGAACTACAGTTCCTGA-3′ (SEQ ID NO:4853) HIF-1α-2535 21 nt Targ: 5′-CTGAGGAAGAACTAAATCCAA-3′ (SEQ ID NO:4854) HIF-1α-2536 21 nt Targ: 5′-TGAGGAAGAACTAAATCCAAA-3′ (SEQ ID NO:4855) HIF-1α-2537 21 nt Targ: 5′-GAGGAAGAACTAAATCCAAAG-3′ (SEQ ID NO:4856) HIF-1α-2538 21 nt Targ: 5′-AGGAAGAACTAAATCCAAAGA-3′ (SEQ ID NO:4857) HIF-1α-2546 21 nt Targ: 5′-CTAAATCCAAAGATACTAGCT-3′ (SEQ ID NO:4858) HIF-1α-2551 21 nt Targ: 5′-TCCAAAGATACTAGCTTTGCA-3′ (SEQ ID NO:4859) HIF-1α-2553 21 nt Targ: 5′-CAAAGATACTAGCTTTGCAGA-3′ (SEQ ID NO:4860) HIF-1α-2554 21 nt Targ: 5′-AAAGATACTAGCTTTGCAGAA-3′ (SEQ ID NO:4861) HIF-1α-2581 21 nt Targ: 5′-GAGAAAGCGAAAAATGGAACA-3′ (SEQ ID NO:4862) HIF-1α-2593 21 nt Targ: 5′-AATGGAACATGATGGTTCACT-3′ (SEQ ID NO:4863) HIF-1α-2599 21 nt Targ: 5′-ACATGATGGTTCACTTTTTCA-3′ (SEQ ID NO:4864) HIF-1α-2611 21 nt Targ: 5′-ACTTTTTCAAGCAGTAGGAAT-3′ (SEQ ID NO:4865) HIF-1α-2620 21 nt Targ: 5′-AGCAGTAGGAATTGGAACATT-3′ (SEQ ID NO:4866) HIF-1α-2621 21 nt Targ: 5′-GCAGTAGGAATTGGAACATTA-3′ (SEQ ID NO:4867) HIF-1α-2622 21 nt Targ: 5′-CAGTAGGAATTGGAACATTAT-3′ (SEQ ID NO:4868) HIF-1α-2680 21 nt Targ: 5′-TTCTTGGAAACGTGTAAAAGG-3′ (SEQ ID NO:4869) HIF-1α-2681 21 nt Targ: 5′-TCTTGGAAACGTGTAAAAGGA-3′ (SEQ ID NO:4870) HIF-1α-2692 21 nt Targ: 5′-TGTAAAAGGATGCAAATCTAG-3′ (SEQ ID NO:4871) HIF-1α-2693 21 nt Targ: 5′-GTAAAAGGATGCAAATCTAGT-3′ (SEQ ID NO:4872) HIF-1α-2698 21 nt Targ: 5′-AGGATGCAAATCTAGTGAACA-3′ (SEQ ID NO:4873) HIF-1α-2702 21 nt Targ: 5′-TGCAAATCTAGTGAACAGAAT-3′ (SEQ ID NO:4874) HIF-1α-2708 21 nt Targ: 5′-TCTAGTGAACAGAATGGAATG-3′ (SEQ ID NO:4875) HIF-1α-2709 21 nt Targ: 5′-CTAGTGAACAGAATGGAATGG-3′ (SEQ ID NO:4876) HIF-1α-2716 21 nt Targ: 5′-ACAGAATGGAATGGAGCAAAA-3′ (SEQ ID NO:4877) HIF-1α-2721 21 nt Targ: 5′-ATGGAATGGAGCAAAAGACAA-3′ (SEQ ID NO:4878) HIF-1α-2723 21 nt Targ: 5′-GGAATGGAGCAAAAGACAATT-3′ (SEQ ID NO:4879) HIF-1α-2724 21 nt Targ: 5′-GAATGGAGCAAAAGACAATTA-3′ (SEQ ID NO:4880) HIF-1α-2725 21 nt Targ: 5′-AATGGAGCAAAAGACAATTAT-3′ (SEQ ID NO:4881) HIF-1α-2726 21 nt Targ: 5′-ATGGAGCAAAAGACAATTATT-3′ (SEQ ID NO:4882) HIF-1α-2738 21 nt Targ: 5′-ACAATTATTTTAATACCCTCT-3′ (SEQ ID NO:4883) HIF-1α-2739 21 nt Targ: 5′-CAATTATTTTAATACCCTCTG-3′ (SEQ ID NO:4884) HIF-1α-2740 21 nt Targ: 5′-AATTATTTTAATACCCTCTGA-3′ (SEQ ID NO:4885) HIF-1α-2742 21 nt Targ: 5′-TTATTTTAATACCCTCTGATT-3′ (SEQ ID NO:4886) HIF-1α-2743 21 nt Targ: 5′-TATTTTAATACCCTCTGATTT-3′ (SEQ ID NO:4887) HIF-1α-2776 21 nt Targ: 5′-GCTGGGGCAATCAATGGATGA-3′ (SEQ ID NO:4888) HIF-1α-2781 21 nt Targ: 5′-GGCAATCAATGGATGAAAGTG-3′ (SEQ ID NO:4889) HIF-1α-2817 21 nt Targ: 5′-CCAGTTATGATTGTGAAGTTA-3′ (SEQ ID NO:4890) HIF-1α-2818 21 nt Targ: 5′-CAGTTATGATTGTGAAGTTAA-3′ (SEQ ID NO:4891) HIF-1α-2826 21 nt Targ: 5′-ATTGTGAAGTTAATGCTCCTA-3′ (SEQ ID NO:4892) HIF-1α-2830 21 nt Targ: 5′-TGAAGTTAATGCTCCTATACA-3′ (SEQ ID NO:4893) HIF-1α-2869 21 nt Targ: 5′-GCAGGGTGAAGAATTACTCAG-3′ (SEQ ID NO:4894) HIF-1α-2875 21 nt Targ: 5′-TGAAGAATTACTCAGAGCTTT-3′ (SEQ ID NO:4895) HIF-1α-2877 21 nt Targ: 5′-AAGAATTACTCAGAGCTTTGG-3′ (SEQ ID NO:4896) HIF-1α-2885 21 nt Targ: 5′-CTCAGAGCTTTGGATCAAGTT-3′ (SEQ ID NO:4897) HIF-1α-2900 21 nt Targ: 5′-CAAGTTAACTGAGCTTTTTCT-3′ (SEQ ID NO:4898) HIF-1α-2902 21 nt Targ: 5′-AGTTAACTGAGCTTTTTCTTA-3′ (SEQ ID NO:4899) HIF-1α-2913 21 nt Targ: 5′-CTTTTTCTTAATTTCATTCCT-3′ (SEQ ID NO:4900) HIF-1α-2918 21 nt Targ: 5′-TCTTAATTTCATTCCTTTTTT-3′ (SEQ ID NO:4901) HIF-1α-2920 21 nt Targ: 5′-TTAATTTCATTCCTTTTTTTG-3′ (SEQ ID NO:4902) HIF-1α-2943 21 nt Targ: 5′-CACTGGTGGCTCATTACCTAA-3′ (SEQ ID NO:4903) HIF-1α-2952 21 nt Targ: 5′-CTCATTACCTAAAGCAGTCTA-3′ (SEQ ID NO:4904) HIF-1α-2953 21 nt Targ: 5′-TCATTACCTAAAGCAGTCTAT-3′ (SEQ ID NO:4905) HIF-1α-2958 21 nt Targ: 5′-ACCTAAAGCAGTCTATTTATA-3′ (SEQ ID NO:4906) HIF-1α-2960 21 nt Targ: 5′-CTAAAGCAGTCTATTTATATT-3′ (SEQ ID NO:4907) HIF-1α-2971 21 nt Targ: 5′-TATTTATATTTTCTACATCTA-3′ (SEQ ID NO:4908) HIF-1α-2972 21 nt Targ: 5′-ATTTATATTTTCTACATCTAA-3′ (SEQ ID NO:4909) HIF-1α-2973 21 nt Targ: 5′-TTTATATTTTCTACATCTAAT-3′ (SEQ ID NO:4910) HIF-1α-2975 21 nt Targ: 5′-TATATTTTCTACATCTAATTT-3′ (SEQ ID NO:4911) HIF-1α-2976 21 nt Targ: 5′-ATATTTTCTACATCTAATTTT-3′ (SEQ ID NO:4912) HIF-1α-3001 21 nt Targ: 5′-GCCTGGCTACAATACTGCACA-3′ (SEQ ID NO:4913) HIF-1α-3022 21 nt Targ: 5′-AACTTGGTTAGTTCAATTTTG-3′ (SEQ ID NO:4914) HIF-1α-3029 21 nt Targ: 5′-TTAGTTCAATTTTGATCCCCT-3′ (SEQ ID NO:4915) HIF-1α-3037 21 nt Targ: 5′-ATTTTGATCCCCTTTCTACTT-3′ (SEQ ID NO:4916) HIF-1α-3038 21 nt Targ: 5′-TTTTGATCCCCTTTCTACTTA-3′ (SEQ ID NO:4917) HIF-1α-3039 21 nt Targ: 5′-TTTGATCCCCTTTCTACTTAA-3′ (SEQ ID NO:4918) HIF-1α-3046 21 nt Targ: 5′-CCCTTTCTACTTAATTTACAT-3′ (SEQ ID NO:4919) HIF-1α-3056 21 nt Targ: 5′-TTAATTTACATTAATGCTCTT-3′ (SEQ ID NO:4920) HIF-1α-3057 21 nt Targ: 5′-TAATTTACATTAATGCTCTTT-3′ (SEQ ID NO:4921) HIF-1α-3063 21 nt Targ: 5′-ACATTAATGCTCTTTTTTAGT-3′ (SEQ ID NO:4922) HIF-1α-3064 21 nt Targ: 5′-CATTAATGCTCTTTTTTAGTA-3′ (SEQ ID NO:4923) HIF-1α-3066 21 nt Targ: 5′-TTAATGCTCTTTTTTAGTATG-3′ (SEQ ID NO:4924) HIF-1α-3074 21 nt Targ: 5′-CTTTTTTAGTATGTTCTTTAA-3′ (SEQ ID NO:4925) HIF-1α-3078 21 nt Targ: 5′-TTTAGTATGTTCTTTAATGCT-3′ (SEQ ID NO:4926) HIF-1α-3079 21 nt Targ: 5′-TTAGTATGTTCTTTAATGCTG-3′ (SEQ ID NO:4927) HIF-1α-3080 21 nt Targ: 5′-TAGTATGTTCTTTAATGCTGG-3′ (SEQ ID NO:4928) HIF-1α-3103 21 nt Targ: 5′-CACAGACAGCTCATTTTCTCA-3′ (SEQ ID NO:4929) HIF-1α-3112 21 nt Targ: 5′-CTCATTTTCTCAGTTTTTTGG-3′ (SEQ ID NO:4930) HIF-1α-3113 21 nt Targ: 5′-TCATTTTCTCAGTTTTTTGGT-3′ (SEQ ID NO:4931) HIF-1α-3114 21 nt Targ: 5′-CATTTTCTCAGTTTTTTGGTA-3′ (SEQ ID NO:4932) HIF-1α-3124 21 nt Targ: 5′-GTTTTTTGGTATTTAAACCAT-3′ (SEQ ID NO:4933) HIF-1α-3128 21 nt Targ: 5′-TTTGGTATTTAAACCATTGCA-3′ (SEQ ID NO:4934) HIF-1α-3129 21 nt Targ: 5′-TTGGTATTTAAACCATTGCAT-3′ (SEQ ID NO:4935) HIF-1α-3134 21 nt Targ: 5′-ATTTAAACCATTGCATTGCAG-3′ (SEQ ID NO:4936) HIF-1α-3146 21 nt Targ: 5′-GCATTGCAGTAGCATCATTTT-3′ (SEQ ID NO:4937) HIF-1α-3151 21 nt Targ: 5′-GCAGTAGCATCATTTTAAAAA-3′ (SEQ ID NO:4938) HIF-1α-3152 21 nt Targ: 5′-CAGTAGCATCATTTTAAAAAA-3′ (SEQ ID NO:4939) HIF-1α-3159 21 nt Targ: 5′-ATCATTTTAAAAAATGCACCT-3′ (SEQ ID NO:4940) HIF-1α-3160 21 nt Targ: 5′-TCATTTTAAAAAATGCACCTT-3′ (SEQ ID NO:4941) HIF-1α-3161 21 nt Targ: 5′-CATTTTAAAAAATGCACCTTT-3′ (SEQ ID NO:4942) HIF-1α-3162 21 nt Targ: 5′-ATTTTAAAAAATGCACCTTTT-3′ (SEQ ID NO:4943) HIF-1α-3163 21 nt Targ: 5′-TTTTAAAAAATGCACCTTTTT-3′ (SEQ ID NO:4944) HIF-1α-3164 21 nt Targ: 5′-TTTAAAAAATGCACCTTTTTA-3′ (SEQ ID NO:4945) HIF-1α-3166 21 nt Targ: 5′-TAAAAAATGCACCTTTTTATT-3′ (SEQ ID NO:4946) HIF-1α-3168 21 nt Targ: 5′-AAAAATGCACCTTTTTATTTA-3′ (SEQ ID NO:4947) HIF-1α-3176 21 nt Targ: 5′-ACCTTTTTATTTATTTATTTT-3′ (SEQ ID NO:4948) HIF-1α-3182 21 nt Targ: 5′-TTATTTATTTATTTTTGGCTA-3′ (SEQ ID NO:4949) HIF-1α-3184 21 nt Targ: 5′-ATTTATTTATTTTTGGCTAGG-3′ (SEQ ID NO:4950) HIF-1α-3185 21 nt Targ: 5′-TTTATTTATTTTTGGCTAGGG-3′ (SEQ ID NO:4951) HIF-1α-3186 21 nt Targ: 5′-TTATTTATTTTTGGCTAGGGA-3′ (SEQ ID NO:4952) HIF-1α-3187 21 nt Targ: 5′-TATTTATTTTTGGCTAGGGAG-3′ (SEQ ID NO:4953) HIF-1α-3202 21 nt Targ: 5′-AGGGAGTTTATCCCTTTTTCG-3′ (SEQ ID NO:4954) HIF-1α-3203 21 nt Targ: 5′-GGGAGTTTATCCCTTTTTCGA-3′ (SEQ ID NO:4955) HIF-1α-3204 21 nt Targ: 5′-GGAGTTTATCCCTTTTTCGAA-3′ (SEQ ID NO:4956) HIF-1α-3205 21 nt Targ: 5′-GAGTTTATCCCTTTTTCGAAT-3′ (SEQ ID NO:4957) HIF-1α-3206 21 nt Targ: 5′-AGTTTATCCCTTTTTCGAATT-3′ (SEQ ID NO:4958) HIF-1α-3207 21 nt Targ: 5′-GTTTATCCCTTTTTCGAATTA-3′ (SEQ ID NO:4959) HIF-1α-3219 21 nt Targ: 5′-TTCGAATTATTTTTAAGAAGA-3′ (SEQ ID NO:4960) HIF-1α-3224 21 nt Targ: 5′-ATTATTTTTAAGAAGATGCCA-3′ (SEQ ID NO:4961) HIF-1α-3225 21 nt Targ: 5′-TTATTTTTAAGAAGATGCCAA-3′ (SEQ ID NO:4962) HIF-1α-3227 21 nt Targ: 5′-ATTTTTAAGAAGATGCCAATA-3′ (SEQ ID NO:4963) HIF-1α-3228 21 nt Targ: 5′-TTTTTAAGAAGATGCCAATAT-3′ (SEQ ID NO:4964) HIF-1α-3230 21 nt Targ: 5′-TTTAAGAAGATGCCAATATAA-3′ (SEQ ID NO:4965) HIF-1α-3231 21 nt Targ: 5′-TTAAGAAGATGCCAATATAAT-3′ (SEQ ID NO:4966) HIF-1α-3233 21 nt Targ: 5′-AAGAAGATGCCAATATAATTT-3′ (SEQ ID NO:4967) HIF-1α-3234 21 nt Targ: 5′-AGAAGATGCCAATATAATTTT-3′ (SEQ ID NO:4968) HIF-1α-3235 21 nt Targ: 5′-GAAGATGCCAATATAATTTTT-3′ (SEQ ID NO:4969) HIF-1α-3242 21 nt Targ: 5′-CCAATATAATTTTTGTAAGAA-3′ (SEQ ID NO:4970) HIF-1α-3246 21 nt Targ: 5′-TATAATTTTTGTAAGAAGGCA-3′ (SEQ ID NO:4971) HIF-1α-3248 21 nt Targ: 5′-TAATTTTTGTAAGAAGGCAGT-3′ (SEQ ID NO:4972) HIF-1α-3277 21 nt Targ: 5′-ATCATGATCATAGGCAGTTGA-3′ (SEQ ID NO:4973) HIF-1α-3279 21 nt Targ: 5′-CATGATCATAGGCAGTTGAAA-3′ (SEQ ID NO:4974) HIF-1α-3283 21 nt Targ: 5′-ATCATAGGCAGTTGAAAAATT-3′ (SEQ ID NO:4975) HIF-1α-3285 21 nt Targ: 5′-CATAGGCAGTTGAAAAATTTT-3′ (SEQ ID NO:4976) HIF-1α-3293 21 nt Targ: 5′-GTTGAAAAATTTTTACACCTT-3′ (SEQ ID NO:4977) HIF-1α-3294 21 nt Targ: 5′-TTGAAAAATTTTTACACCTTT-3′ (SEQ ID NO:4978) HIF-1α-3295 21 nt Targ: 5′-TGAAAAATTTTTACACCTTTT-3′ (SEQ ID NO:4979) HIF-1α-3296 21 nt Targ: 5′-GAAAAATTTTTACACCTTTTT-3′ (SEQ ID NO:4980) HIF-1α-3297 21 nt Targ: 5′-AAAAATTTTTACACCTTTTTT-3′ (SEQ ID NO:4981) HIF-1α-3311 21 nt Targ: 5′-CTTTTTTTTCACATTTTACAT-3′ (SEQ ID NO:4982) HIF-1α-3312 21 nt Targ: 5′-TTTTTTTTCACATTTTACATA-3′ (SEQ ID NO:4983) HIF-1α-3313 21 nt Targ: 5′-TTTTTTTCACATTTTACATAA-3′ (SEQ ID NO:4984) HIF-1α-3314 21 nt Targ: 5′-TTTTTTCACATTTTACATAAA-3′ (SEQ ID NO:4985) HIF-1α-3320 21 nt Targ: 5′-CACATTTTACATAAATAATAA-3′ (SEQ ID NO:4986) HIF-1α-3359 21 nt Targ: 5′-TGGTAGCCACAATTGCACAAT-3′ (SEQ ID NO:4987) HIF-1α-3375 21 nt Targ: 5′-ACAATATATTTTCTTAAAAAA-3′ (SEQ ID NO:4988) HIF-1α-3385 21 nt Targ: 5′-TTCTTAAAAAATACCAGCAGT-3′ (SEQ ID NO:4989) HIF-1α-3400 21 nt Targ: 5′-AGCAGTTACTCATGGAATATA-3′ (SEQ ID NO:4990) HIF-1α-3408 21 nt Targ: 5′-CTCATGGAATATATTCTGCGT-3′ (SEQ ID NO:4991) HIF-1α-3409 21 nt Targ: 5′-TCATGGAATATATTCTGCGTT-3′ (SEQ ID NO:4992) HIF-1α-3410 21 nt Targ: 5′-CATGGAATATATTCTGCGTTT-3′ (SEQ ID NO:4993) HIF-1α-3411 21 nt Targ: 5′-ATGGAATATATTCTGCGTTTA-3′ (SEQ ID NO:4994) HIF-1α-3412 21 nt Targ: 5′-TGGAATATATTCTGCGTTTAT-3′ (SEQ ID NO:4995) HIF-1α-3413 21 nt Targ: 5′-GGAATATATTCTGCGTTTATA-3′ (SEQ ID NO:4996) HIF-1α-3414 21 nt Targ: 5′-GAATATATTCTGCGTTTATAA-3′ (SEQ ID NO:4997) HIF-1α-3429 21 nt Targ: 5′-TTATAAAACTAGTTTTTAAGA-3′ (SEQ ID NO:4998) HIF-1α-3435 21 nt Targ: 5′-AACTAGTTTTTAAGAAGAAAT-3′ (SEQ ID NO:4999) HIF-1α-3436 21 nt Targ: 5′-ACTAGTTTTTAAGAAGAAATT-3′ (SEQ ID NO:5000) HIF-1α-3437 21 nt Targ: 5′-CTAGTTTTTAAGAAGAAATTT-3′ (SEQ ID NO:5001) HIF-1α-3438 21 nt Targ: 5′-TAGTTTTTAAGAAGAAATTTT-3′ (SEQ ID NO:5002) HIF-1α-3441 21 nt Targ: 5′-TTTTTAAGAAGAAATTTTTTT-3′ (SEQ ID NO:5003) HIF-1α-3447 21 nt Targ: 5′-AGAAGAAATTTTTTTTGGCCT-3′ (SEQ ID NO:5004) HIF-1α-3449 21 nt Targ: 5′-AAGAAATTTTTTTTGGCCTAT-3′ (SEQ ID NO:5005) HIF-1α-3451 21 nt Targ: 5′-GAAATTTTTTTTGGCCTATGA-3′ (SEQ ID NO:5006) HIF-1α-3453 21 nt Targ: 5′-AATTTTTTTTGGCCTATGAAA-3′ (SEQ ID NO:5007) HIF-1α-3456 21 nt Targ: 5′-TTTTTTTGGCCTATGAAATTG-3′ (SEQ ID NO:5008) HIF-1α-3457 21 nt Targ: 5′-TTTTTTGGCCTATGAAATTGT-3′ (SEQ ID NO:5009) HIF-1α-3458 21 nt Targ: 5′-TTTTTGGCCTATGAAATTGTT-3′ (SEQ ID NO:5010) HIF-1α-3459 21 nt Targ: 5′-TTTTGGCCTATGAAATTGTTA-3′ (SEQ ID NO:5011) HIF-1α-3464 21 nt Targ: 5′-GCCTATGAAATTGTTAAACCT-3′ (SEQ ID NO:5012) HIF-1α-3466 21 nt Targ: 5′-CTATGAAATTGTTAAACCTGG-3′ (SEQ ID NO:5013) HIF-1α-3470 21 nt Targ: 5′-GAAATTGTTAAACCTGGAACA-3′ (SEQ ID NO:5014) HIF-1α-3471 21 nt Targ: 5′-AAATTGTTAAACCTGGAACAT-3′ (SEQ ID NO:5015) HIF-1α-3481 21 nt Targ: 5′-ACCTGGAACATGACATTGTTA-3′ (SEQ ID NO:5016) HIF-1α-3487 21 nt Targ: 5′-AACATGACATTGTTAATCATA-3′ (SEQ ID NO:5017) HIF-1α-3488 21 nt Targ: 5′-ACATGACATTGTTAATCATAT-3′ (SEQ ID NO:5018) HIF-1α-3492 21 nt Targ: 5′-GACATTGTTAATCATATAATA-3′ (SEQ ID NO:5019) HIF-1α-3494 21 nt Targ: 5′-CATTGTTAATCATATAATAAT-3′ (SEQ ID NO:5020) HIF-1α-3495 21 nt Targ: 5′-ATTGTTAATCATATAATAATG-3′ (SEQ ID NO:5021) HIF-1α-3496 21 nt Targ: 5′-TTGTTAATCATATAATAATGA-3′ (SEQ ID NO:5022) HIF-1α-3503 21 nt Targ: 5′-TCATATAATAATGATTCTTAA-3′ (SEQ ID NO:5023) HIF-1α-3504 21 nt Targ: 5′-CATATAATAATGATTCTTAAA-3′ (SEQ ID NO:5024) HIF-1α-3508 21 nt Targ: 5′-TAATAATGATTCTTAAATGCT-3′ (SEQ ID NO:5025) HIF-1α-3511 21 nt Targ: 5′-TAATGATTCTTAAATGCTGTA-3′ (SEQ ID NO:5026) HIF-1α-3512 21 nt Targ: 5′-AATGATTCTTAAATGCTGTAT-3′ (SEQ ID NO:5027) HIF-1α-3513 21 nt Targ: 5′-ATGATTCTTAAATGCTGTATG-3′ (SEQ ID NO:5028) HIF-1α-3518 21 nt Targ: 5′-TCTTAAATGCTGTATGGTTTA-3′ (SEQ ID NO:5029) HIF-1α-3519 21 nt Targ: 5′-CTTAAATGCTGTATGGTTTAT-3′ (SEQ ID NO:5030) HIF-1α-3521 21 nt Targ: 5′-TAAATGCTGTATGGTTTATTA-3′ (SEQ ID NO:5031) HIF-1α-3528 21 nt Targ: 5′-TGTATGGTTTATTATTTAAAT-3′ (SEQ ID NO:5032) HIF-1α-3530 21 nt Targ: 5′-TATGGTTTATTATTTAAATGG-3′ (SEQ ID NO:5033) HIF-1α-3531 21 nt Targ: 5′-ATGGTTTATTATTTAAATGGG-3′ (SEQ ID NO:5034) HIF-1α-3533 21 nt Targ: 5′-GGTTTATTATTTAAATGGGTA-3′ (SEQ ID NO:5035) HIF-1α-3534 21 nt Targ: 5′-GTTTATTATTTAAATGGGTAA-3′ (SEQ ID NO:5036) HIF-1α-3539 21 nt Targ: 5′-TTATTTAAATGGGTAAAGCCA-3′ (SEQ ID NO:5037) HIF-1α-3545 21 nt Targ: 5′-AAATGGGTAAAGCCATTTACA-3′ (SEQ ID NO:5038) HIF-1α-3548 21 nt Targ: 5′-TGGGTAAAGCCATTTACATAA-3′ (SEQ ID NO:5039) HIF-1α-3550 21 nt Targ: 5′-GGTAAAGCCATTTACATAATA-3′ (SEQ ID NO:5040) HIF-1α-3551 21 nt Targ: 5′-GTAAAGCCATTTACATAATAT-3′ (SEQ ID NO:5041) HIF-1α-3556 21 nt Targ: 5′-GCCATTTACATAATATAGAAA-3′ (SEQ ID NO:5042) HIF-1α-3565 21 nt Targ: 5′-ATAATATAGAAAGATATGCAT-3′ (SEQ ID NO:5043) HIF-1α-3566 21 nt Targ: 5′-TAATATAGAAAGATATGCATA-3′ (SEQ ID NO:5044) HIF-1α-3567 21 nt Targ: 5′-AATATAGAAAGATATGCATAT-3′ (SEQ ID NO:5045) HIF-1α-3571 21 nt Targ: 5′-TAGAAAGATATGCATATATCT-3′ (SEQ ID NO:5046) HIF-1α-3574 21 nt Targ: 5′-AAAGATATGCATATATCTAGA-3′ (SEQ ID NO:5047) HIF-1α-3575 21 nt Targ: 5′-AAGATATGCATATATCTAGAA-3′ (SEQ ID NO:5048) HIF-1α-3576 21 nt Targ: 5′-AGATATGCATATATCTAGAAG-3′ (SEQ ID NO:5049) HIF-1α-3581 21 nt Targ: 5′-TGCATATATCTAGAAGGTATG-3′ (SEQ ID NO:5050) HIF-1α-3582 21 nt Targ: 5′-GCATATATCTAGAAGGTATGT-3′ (SEQ ID NO:5051) HIF-1α-3589 21 nt Targ: 5′-TCTAGAAGGTATGTGGCATTT-3′ (SEQ ID NO:5052) HIF-1α-3593 21 nt Targ: 5′-GAAGGTATGTGGCATTTATTT-3′ (SEQ ID NO:5053) HIF-1α-3597 21 nt Targ: 5′-GTATGTGGCATTTATTTGGAT-3′ (SEQ ID NO:5054) HIF-1α-3599 21 nt Targ: 5′-ATGTGGCATTTATTTGGATAA-3′ (SEQ ID NO:5055) HIF-1α-3607 21 nt Targ: 5′-TTTATTTGGATAAAATTCTCA-3′ (SEQ ID NO:5056) HIF-1α-3613 21 nt Targ: 5′-TGGATAAAATTCTCAATTCAG-3′ (SEQ ID NO:5057) HIF-1α-3615 21 nt Targ: 5′-GATAAAATTCTCAATTCAGAG-3′ (SEQ ID NO:5058) HIF-1α-3617 21 nt Targ: 5′-TAAAATTCTCAATTCAGAGAA-3′ (SEQ ID NO:5059) HIF-1α-3625 21 nt Targ: 5′-TCAATTCAGAGAAATCATCTG-3′ (SEQ ID NO:5060) HIF-1α-3629 21 nt Targ: 5′-TTCAGAGAAATCATCTGATGT-3′ (SEQ ID NO:5061) HIF-1α-3634 21 nt Targ: 5′-AGAAATCATCTGATGTTTCTA-3′ (SEQ ID NO:5062) HIF-1α-3642 21 nt Targ: 5′-TCTGATGTTTCTATAGTCACT-3′ (SEQ ID NO:5063) HIF-1α-3643 21 nt Targ: 5′-CTGATGTTTCTATAGTCACTT-3′ (SEQ ID NO:5064) HIF-1α-3671 21 nt Targ: 5′-TCAAAAGAAAACAATACCCTA-3′ (SEQ ID NO:5065) HIF-1α-3673 21 nt Targ: 5′-AAAAGAAAACAATACCCTATG-3′ (SEQ ID NO:5066) HIF-1α-3674 21 nt Targ: 5′-AAAGAAAACAATACCCTATGT-3′ (SEQ ID NO:5067) HIF-1α-3676 21 nt Targ: 5′-AGAAAACAATACCCTATGTAG-3′ (SEQ ID NO:5068) HIF-1α-3680 21 nt Targ: 5′-AACAATACCCTATGTAGTTGT-3′ (SEQ ID NO:5069) HIF-1α-3688 21 nt Targ: 5′-CCTATGTAGTTGTGGAAGTTT-3′ (SEQ ID NO:5070) HIF-1α-3689 21 nt Targ: 5′-CTATGTAGTTGTGGAAGTTTA-3′ (SEQ ID NO:5071) HIF-1α-3694 21 nt Targ: 5′-TAGTTGTGGAAGTTTATGCTA-3′ (SEQ ID NO:5072) HIF-1α-3695 21 nt Targ: 5′-AGTTGTGGAAGTTTATGCTAA-3′ (SEQ ID NO:5073) HIF-1α-3697 21 nt Targ: 5′-TTGTGGAAGTTTATGCTAATA-3′ (SEQ ID NO:5074) HIF-1α-3699 21 nt Targ: 5′-GTGGAAGTTTATGCTAATATT-3′ (SEQ ID NO:5075) HIF-1α-3700 21 nt Targ: 5′-TGGAAGTTTATGCTAATATTG-3′ (SEQ ID NO:5076) HIF-1α-3701 21 nt Targ: 5′-GGAAGTTTATGCTAATATTGT-3′ (SEQ ID NO:5077) HIF-1α-3703 21 nt Targ: 5′-AAGTTTATGCTAATATTGTGT-3′ (SEQ ID NO:5078) HIF-1α-3710 21 nt Targ: 5′-TGCTAATATTGTGTAACTGAT-3′ (SEQ ID NO:5079) HIF-1α-3712 21 nt Targ: 5′-CTAATATTGTGTAACTGATAT-3′ (SEQ ID NO:5080) HIF-1α-3714 21 nt Targ: 5′-AATATTGTGTAACTGATATTA-3′ (SEQ ID NO:5081) HIF-1α-3724 21 nt Targ: 5′-AACTGATATTAAACCTAAATG-3′ (SEQ ID NO:5082) HIF-1α-3756 21 nt Targ: 5′-CTGTTGGTATAAAGATATTTT-3′ (SEQ ID NO:5083) HIF-1α-3761 21 nt Targ: 5′-GGTATAAAGATATTTTGAGCA-3′ (SEQ ID NO:5084) HIF-1α-3765 21 nt Targ: 5′-TAAAGATATTTTGAGCAGACT-3′ (SEQ ID NO:5085) HIF-1α-3766 21 nt Targ: 5′-AAAGATATTTTGAGCAGACTG-3′ (SEQ ID NO:5086) HIF-1α-3767 21 nt Targ: 5′-AAGATATTTTGAGCAGACTGT-3′ (SEQ ID NO:5087) HIF-1α-3772 21 nt Targ: 5′-ATTTTGAGCAGACTGTAAACA-3′ (SEQ ID NO:5088) HIF-1α-3774 21 nt Targ: 5′-TTTGAGCAGACTGTAAACAAG-3′ (SEQ ID NO:5089) HIF-1α-3778 21 nt Targ: 5′-AGCAGACTGTAAACAAGAAAA-3′ (SEQ ID NO:5090) HIF-1α-3782 21 nt Targ: 5′-GACTGTAAACAAGAAAAAAAA-3′ (SEQ ID NO:5091) HIF-1α-3783 21 nt Targ: 5′-ACTGTAAACAAGAAAAAAAAA-3′ (SEQ ID NO:5092) HIF-1α-3795 21 nt Targ: 5′-AAAAAAAAAATCATGCATTCT-3′ (SEQ ID NO:5093) HIF-1α-3796 21 nt Targ: 5′-AAAAAAAAATCATGCATTCTT-3′ (SEQ ID NO:5094) HIF-1α-3804 21 nt Targ: 5′-ATCATGCATTCTTAGCAAAAT-3′ (SEQ ID NO:5095) HIF-1α-3812 21 nt Targ: 5′-TTCTTAGCAAAATTGCCTAGT-3′ (SEQ ID NO:5096) HIF-1α-3813 21 nt Targ: 5′-TCTTAGCAAAATTGCCTAGTA-3′ (SEQ ID NO:5097) HIF-1α-3818 21 nt Targ: 5′-GCAAAATTGCCTAGTATGTTA-3′ (SEQ ID NO:5098) HIF-1α-3820 21 nt Targ: 5′-AAAATTGCCTAGTATGTTAAT-3′ (SEQ ID NO:5099) HIF-1α-3821 21 nt Targ: 5′-AAATTGCCTAGTATGTTAATT-3′ (SEQ ID NO:5100) HIF-1α-3827 21 nt Targ: 5′-CCTAGTATGTTAATTTGCTCA-3′ (SEQ ID NO:5101) HIF-1α-3828 21 nt Targ: 5′-CTAGTATGTTAATTTGCTCAA-3′ (SEQ ID NO:5102) HIF-1α-3829 21 nt Targ: 5′-TAGTATGTTAATTTGCTCAAA-3′ (SEQ ID NO:5103) HIF-1α-3835 21 nt Targ: 5′-GTTAATTTGCTCAAAATACAA-3′ (SEQ ID NO:5104) HIF-1α-3836 21 nt Targ: 5′-TTAATTTGCTCAAAATACAAT-3′ (SEQ ID NO:5105) HIF-1α-3838 21 nt Targ: 5′-AATTTGCTCAAAATACAATGT-3′ (SEQ ID NO:5106) HIF-1α-3844 21 nt Targ: 5′-CTCAAAATACAATGTTTGATT-3′ (SEQ ID NO:5107) HIF-1α-3846 21 nt Targ: 5′-CAAAATACAATGTTTGATTTT-3′ (SEQ ID NO:5108) HIF-1α-3847 21 nt Targ: 5′-AAAATACAATGTTTGATTTTA-3′ (SEQ ID NO:5109) HIF-1α-3853 21 nt Targ: 5′-CAATGTTTGATTTTATGCACT-3′ (SEQ ID NO:5110) HIF-1α-3854 21 nt Targ: 5′-AATGTTTGATTTTATGCACTT-3′ (SEQ ID NO:5111) HIF-1α-3864 21 nt Targ: 5′-TTTATGCACTTTGTCGCTATT-3′ (SEQ ID NO:5112) HIF-1α-3872 21 nt Targ: 5′-CTTTGTCGCTATTAACATCCT-3′ (SEQ ID NO:5113) HIF-1α-3891 21 nt Targ: 5′-CTTTTTTTCATGTAGATTTCA-3′ (SEQ ID NO:5114) HIF-1α-3892 21 nt Targ: 5′-TTTTTTTCATGTAGATTTCAA-3′ (SEQ ID NO:5115) HIF-1α-3897 21 nt Targ: 5′-TTCATGTAGATTTCAATAATT-3′ (SEQ ID NO:5116) HIF-1α-3898 21 nt Targ: 5′-TCATGTAGATTTCAATAATTG-3′ (SEQ ID NO:5117) HIF-1α-3899 21 nt Targ: 5′-CATGTAGATTTCAATAATTGA-3′ (SEQ ID NO:5118) HIF-1α-3900 21 nt Targ: 5′-ATGTAGATTTCAATAATTGAG-3′ (SEQ ID NO:5119) HIF-1α-3901 21 nt Targ: 5′-TGTAGATTTCAATAATTGAGT-3′ (SEQ ID NO:5120) HIF-1α-3902 21 nt Targ: 5′-GTAGATTTCAATAATTGAGTA-3′ (SEQ ID NO:5121) HIF-1α-3903 21 nt Targ: 5′-TAGATTTCAATAATTGAGTAA-3′ (SEQ ID NO:5122) HIF-1α-3904 21 nt Targ: 5′-AGATTTCAATAATTGAGTAAT-3′ (SEQ ID NO:5123) HIF-1α-3910 21 nt Targ: 5′-CAATAATTGAGTAATTTTAGA-3′ (SEQ ID NO:5124) HIF-1α-3914 21 nt Targ: 5′-AATTGAGTAATTTTAGAAGCA-3′ (SEQ ID NO:5125) HIF-1α-3915 21 nt Targ: 5′-ATTGAGTAATTTTAGAAGCAT-3′ (SEQ ID NO:5126) HIF-1α-3917 21 nt Targ: 5′-TGAGTAATTTTAGAAGCATTA-3′ (SEQ ID NO:5127) HIF-1α-3921 21 nt Targ: 5′-TAATTTTAGAAGCATTATTTT-3′ (SEQ ID NO:5128) HIF-1α-3925 21 nt Targ: 5′-TTTAGAAGCATTATTTTAGGA-3′ (SEQ ID NO:5129) HIF-1α-3927 21 nt Targ: 5′-TAGAAGCATTATTTTAGGAAT-3′ (SEQ ID NO:5130) HIF-1α-3931 21 nt Targ: 5′-AGCATTATTTTAGGAATATAT-3′ (SEQ ID NO:5131) HIF-1α-3933 21 nt Targ: 5′-CATTATTTTAGGAATATATAG-3′ (SEQ ID NO:5132) HIF-1α-3941 21 nt Targ: 5′-TAGGAATATATAGTTGTCACA-3′ (SEQ ID NO:5133) HIF-1α-3942 21 nt Targ: 5′-AGGAATATATAGTTGTCACAG-3′ (SEQ ID NO:5134) HIF-1α-3943 21 nt Targ: 5′-GGAATATATAGTTGTCACAGT-3′ (SEQ ID NO:5135) HIF-1α-3945 21 nt Targ: 5′-AATATATAGTTGTCACAGTAA-3′ (SEQ ID NO:5136) HIF-1α-3946 21 nt Targ: 5′-ATATATAGTTGTCACAGTAAA-3′ (SEQ ID NO:5137) HIF-1α-3951 21 nt Targ: 5′-TAGTTGTCACAGTAAATATCT-3′ (SEQ ID NO:5138) HIF-1α-3952 21 nt Targ: 5′-AGTTGTCACAGTAAATATCTT-3′ (SEQ ID NO:5139) HIF-1α-3962 21 nt Targ: 5′-GTAAATATCTTGTTTTTTCTA-3′ (SEQ ID NO:5140) HIF-1α-3963 21 nt Targ: 5′-TAAATATCTTGTTTTTTCTAT-3′ (SEQ ID NO:5141) HIF-1α-3968 21 nt Targ: 5′-ATCTTGTTTTTTCTATGTACA-3′ (SEQ ID NO:5142) HIF-1α-3969 21 nt Targ: 5′-TCTTGTTTTTTCTATGTACAT-3′ (SEQ ID NO:5143) HIF-1α-3970 21 nt Targ: 5′-CTTGTTTTTTCTATGTACATT-3′ (SEQ ID NO:5144) HIF-1α-3971 21 nt Targ: 5′-TTGTTTTTTCTATGTACATTG-3′ (SEQ ID NO:5145) HIF-1α-3978 21 nt Targ: 5′-TTCTATGTACATTGTACAAAT-3′ (SEQ ID NO:5146) HIF-1α-3979 21 nt Targ: 5′-TCTATGTACATTGTACAAATT-3′ (SEQ ID NO:5147) HIF-1α-3997 21 nt Targ: 5′-ATTTTTCATTCCTTTTGCTCT-3′ (SEQ ID NO:5148) HIF-1α-4021 21 nt Targ: 5′-TGGTTGGATCTAACACTAACT-3′ (SEQ ID NO:5149) HIF-1α-4022 21 nt Targ: 5′-GGTTGGATCTAACACTAACTG-3′ (SEQ ID NO:5150) HIF-1α-4024 21 nt Targ: 5′-TTGGATCTAACACTAACTGTA-3′ (SEQ ID NO:5151) HIF-1α-4040 21 nt Targ: 5′-CTGTATTGTTTTGTTACATCA-3′ (SEQ ID NO:5152) HIF-1α-4041 21 nt Targ: 5′-TGTATTGTTTTGTTACATCAA-3′ (SEQ ID NO:5153) HIF-1α-4042 21 nt Targ: 5′-GTATTGTTTTGTTACATCAAA-3′ (SEQ ID NO:5154) HIF-1α-4044 21 nt Targ: 5′-ATTGTTTTGTTACATCAAATA-3′ (SEQ ID NO:5155) HIF-1α-4072 21 nt Targ: 5′-TCTGTGGACCAGGCAAAAAAA-3′ (SEQ ID NO:5156) HIF-1α-4073 21 nt Targ: 5′-CTGTGGACCAGGCAAAAAAAA-3′ (SEQ ID NO:5157) HIF-1α-4079 21 nt Targ: 5′-ACCAGGCAAAAAAAAAAAAAA-3′ (SEQ ID NO:5158) HIF-1α-2610t2 21 nt Targ: 5′-CACTTTTTCAAGCAGTAGGAA-3′ (SEQ ID NO:5159) HIF-1α-2611t2 21 nt Targ: 5′-ACTTTTTCAAGCAGTAGGAAT-3′ (SEQ ID NO:5160) HIF-1α-2616t2 21 nt Targ: 5′-TTCAAGCAGTAGGAATTATTT-3′ (SEQ ID NO:5161) HIF-1α-2620t2 21 nt Targ: 5′-AGCAGTAGGAATTATTTAGCA-3′ (SEQ ID NO:5162) HIF-1α-2622t2 21 nt Targ: 5′-CAGTAGGAATTATTTAGCATG-3′ (SEQ ID NO:5163) HIF-1α-2623t2 21 nt Targ: 5′-AGTAGGAATTATTTAGCATGT-3′ (SEQ ID NO:5164) HIF-1α-2624t2 21 nt Targ: 5′-GTAGGAATTATTTAGCATGTA-3′ (SEQ ID NO:5165)

TABLE 6 Selected Human Anti-HIF-1α “Blunt/Fray” DsiRNAs (HIF-1αVariant 1)

TABLE 7 Selected Human Anti-HIF-1α “Blunt/Blunt” DsiRNAs(HIF-1α Variant 1) 5′-GUGAAGACAUCGCGGGGACCGAUUCAC-3′ (SEQ ID NO: 1321)3′-CACUUCUGUAGCGCCCCUGGCUAAGUG-5′ (SEQ ID NO: 27) HIF-1α-403 Target:5′-GTGAAGACATCGCGGGGACCGATTCAC-3′ (SEQ ID NO: 783)5′-AAGUUCUGAACGUCGAAAAGAAAAGUC-3′ (SEQ ID NO: 1322)3′-UUCAAGACUUGCAGCUUUUCUUUUCAG-5′ (SEQ ID NO: 33) HIF-1α-469 Target:5′-AAGTTCTGAACGTCGAAAAGAAAAGTC-3′ (SEQ ID NO: 789)5′-UCUGAAGUUUUUUAUGAGCUUGCUCAU-3′ (SEQ ID NO: 1323)3′-AGACUUCAAAAAAUACUCGAACGAGUA-5′ (SEQ ID NO: 39) HIF-1α-530 Target:5′-TCTGAAGTTTTTTATGAGCTTGCTCAT-3′ (SEQ ID NO: 795)5′-AAGUUUUUUAUGAGCUUGCUCAUCAGU-3′ (SEQ ID NO: 1324)3′-UUCAAAAAAUACUCGAACGAGUAGUCA-5′ (SEQ ID NO: 41) HIF-1α-534 Target:5′-AAGTTTTTTATGAGCTTGCTCATCAGT-3′ (SEQ ID NO: 797)5′-GAUGAAUUGCUUUUAUUUGAAAGCCUU-3′ (SEQ ID NO: 1325)3′-CUACUUAACGAAAAUAAACUUUCGGAA-5′ (SEQ ID NO: 55) HIF-1α-691 Target:5′-GATGAATTGCTTTTATTTGAAAGCCTT-3′ (SEQ ID NO: 811)5′-AAGCCUUGGAUGGUUUUGUUAUGGUUC-3′ (SEQ ID NO: 1326)3′-UUCGGAACCUACCAAAACAAUACCAAG-5′ (SEQ ID NO: 57) HIF-1α-711 Target:5′-AAGCCTTGGATGGTTTTGTTATGGTTC-3′ (SEQ ID NO: 813)5′-GCCUUGGAUGGUUUUGUUAUGGUUCUC-3′ (SEQ ID NO: 1327)3′-CGGAACCUACCAAAACAAUACCAAGAG-5′ (SEQ ID NO: 58) HIF-1α-713 Target:5′-GCCTTGGATGGTTTTGTTATGGTTCTC-3′ (SEQ ID NO: 814)5′-CUUGGAUGGUUUUGUUAUGGUUCUCAC-3′ (SEQ ID NO: 1328)3′-GAACCUACCAAAACAAUACCAAGAGUG-5′ (SEQ ID NO: 59) HIF-1α-715 Target:5′-CTTGGATGGTTTTGTTATGGTTCTCAC-3′ (SEQ ID NO: 815)5′-UGGAUGGUUUUGUUAUGGUUCUCACAG-3′ (SEQ ID NO: 1329)3′-ACCUACCAAAACAAUACCAAGAGUGUC-5′ (SEQ ID NO: 60) HIF-1α-717 Target:5′-TGGATGGTTTTGTTATGGTTCTCACAG-3′ (SEQ ID NO: 816)5′-UGAUUUACAUUUCUGAUAAUGUGAACA-3′ (SEQ ID NO: 1330)3′-ACUAAAUGUAAAGACUAUUACACUUGU-5′ (SEQ ID NO: 61) HIF-1α-756 Target:5′-TGATTTACATTTCTGATAATGTGAACA-3′ (SEQ ID NO: 817)5′-GUGUUUGAUUUUACUCAUCCAUGUGAC-3′ (SEQ ID NO: 1331)3′-CACAAACUAAAAUGAGUAGGUACACUG-5′ (SEQ ID NO: 64) HIF-1α-824 Target:5′-GTGTTTGATTTTACTCATCCATGTGAC-3′ (SEQ ID NO: 820)5′-ACAGUAACCAACCUCAGUGUGGGUAUA-3′ (SEQ ID NO: 1332)3′-UGUCAUUGGUUGGAGUCACACCCAUAU-5′ (SEQ ID NO: 88) HIF-1α-1041 Target:5′-ACAGTAACCAACCTCAGTGTGGGTATA-3′ (SEQ ID NO: 844)5′-GGUGCUGAUUUGUGAACCCAUUCCUCA-3′ (SEQ ID NO: 1333)3′-CCACGACUAAACACUUGGGUAAGGAGU-5′ (SEQ ID NO: 97) HIF-1α-1090 Target:5′-GGTGCTGATTTGTGAACCCATTCCTCA-3′ (SEQ ID NO: 853)5′-UAUUAUCAUGCUUUGGACUCUGAUCAU-3′ (SEQ ID NO: 1334)3′-AUAAUAGUACGAAACCUGAGACUAGUA-5′ (SEQ ID NO: 118) HIF-1α-1262 Target:5′-TATTATCATGCTTTGGACTCTGATCAT-3′ (SEQ ID NO: 874)5′-CAUGCUUUGGACUCUGAUCAUCUGACC-3′ (SEQ ID NO: 1335)3′-GUACGAAACCUGAGACUAGUAGACUGG-5′ (SEQ ID NO: 120) HIF-1α-1268 Target:5′-CATGCTTTGGACTCTGATCATCTGACC-3′ (SEQ ID NO: 876)5′-GCUUUGGACUCUGAUCAUCUGACCAAA-3′ (SEQ ID NO: 1336)3′-CGAAACCUGAGACUAGUAGACUGGUUU-5′ (SEQ ID NO: 121) HIF-1α-1271 Target:5′-GCTTTGGACTCTGATCATCTGACCAAA-3′ (SEQ ID NO: 877)5′-UACAGGAUGCUUGCCAAAAGAGGUGGA-3′ (SEQ ID NO: 1337)3′-AUGUCCUACGAACGGUUUUCUCCACCU-5′ (SEQ ID NO: 145) HIF-1α-1343 Target:5′-TACAGGATGCTTGCCAAAAGAGGTGGA-3′ (SEQ ID NO: 901)5′-GGAUAUGUCUGGGUUGAAACUCAAGCA-3′ (SEQ ID NO: 1338)3′-CCUAUACAGACCCAACUUUGAGUUCGU-5′ (SEQ ID NO: 157) HIF-1α-1367 Target:5′-GGATATGTCTGGGTTGAAACTCAAGCA-3′ (SEQ ID NO: 913)5′-AUAUGUCUGGGUUGAAACUCAAGCAAC-3′ (SEQ ID NO: 1339)3′-UAUACAGACCCAACUUUGAGUUCGUUG-5′ (SEQ ID NO: 158) HIF-1α-1369 Target:5′-ATATGTCTGGGTTGAAACTCAAGCAAC-3′ (SEQ ID NO: 914)5′-GGGUUGAAACUCAAGCAACUGUCAUAU-3′ (SEQ ID NO: 1340)3′-CCCAACUUUGAGUUCGUUGACAGUAUA-5′ (SEQ ID NO: 162) HIF-1α-1377 Target:5′-GGGTTGAAACTCAAGCAACTGTCATAT-3′ (SEQ ID NO: 918)5′-GUUGAAACUCAAGCAACUGUCAUAUAU-3′ (SEQ ID NO: 1341)3′-CAACUUUGAGUUCGUUGACAGUAUAUA-5′ (SEQ ID NO: 163) HIF-1α-1379 Target:5′-GTTGAAACTCAAGCAACTGTCATATAT-3′ (SEQ ID NO: 919)5′-AGCACGACUUGAUUUUCUCCCUUCAAC-3′ (SEQ ID NO: 1342)3′-UCGUGCUGAACUAAAAGAGGGAAGUUG-5′ (SEQ ID NO: 175) HIF-1α-1470 Target:5′-AGCACGACTTGATTTTCTCCCTTCAAC-3′ (SEQ ID NO: 931)5′-ACUUGAUUUUCUCCCUUCAACAAACAG-3′ (SEQ ID NO: 1343)3′-UGAACUAAAAGAGGGAAGUUGUUUGUC-5′ (SEQ ID NO: 178) HIF-1α-1476 Target:5′-ACTTGATTTTCTCCCTTCAACAAACAG-3′ (SEQ ID NO: 934)5′-UUGAUUUUCUCCCUUCAACAAACAGAA-3′ (SEQ ID NO: 1344)3′-AACUAAAAGAGGGAAGUUGUUUGUCUU-5′ (SEQ ID NO: 179) HIF-1α-1478 Target:5′-TTGATTTTCTCCCTTCAACAAACAGAA-3′ (SEQ ID NO: 935)5′-UUUUCUCCCUUCAACAAACAGAAUGUG-3′ (SEQ ID NO: 1345)3′-AAAAGAGGGAAGUUGUUUGUCUUACAC-5′ (SEQ ID NO: 181) HIF-1α-1482 Target:5′-TTTTCTCCCTTCAACAAACAGAATGTG-3′ (SEQ ID NO: 937)5′-CACAAUCAUAUCUUUAGAUUUUGGCAG-3′ (SEQ ID NO: 1346)3′-GUGUUAGUAUAGAAAUCUAAAACCGUC-5′ (SEQ ID NO: 185) HIF-1α-1648 Target:5′-CACAATCATATCTTTAGATTTTGGCAG-3′ (SEQ ID NO: 941)5′-AAGAAGUUGCAUUAAAAUUAGAACCAA-3′ (SEQ ID NO: 1347)3′-UUCUUCAACGUAAUUUUAAUCUUGGUU-5′ (SEQ ID NO: 194) HIF-1α-1845 Target:5′-AAGAAGTTGCATTAAAATTAGAACCAA-3′ (SEQ ID NO: 950)5′-GGAAGCACUAGACAAAGUUCACCUGAG-3′ (SEQ ID NO: 1348)3′-CCUUCGUGAUCUGUUUCAAGUGGACUC-5′ (SEQ ID NO: 197) HIF-1α-1940 Target:5′-GGAAGCACTAGACAAAGTTCACCTGAG-3′ (SEQ ID NO: 953)5′-GCACUAGACAAAGUUCACCUGAGCCUA-3′ (SEQ ID NO: 1349)3′-CGUGAUCUGUUUCAAGUGGACUCGGAU-5′ (SEQ ID NO: 199) HIF-1α-1944 Target:5′-GCACTAGACAAAGTTCACCTGAGCCTA-3′ (SEQ ID NO: 955)5′-ACUAGACAAAGUUCACCUGAGCCUAAU-3′ (SEQ ID NO: 1350)3′-UGAUCUGUUUCAAGUGGACUCGGAUUA-5′ (SEQ ID NO: 200) HIF-1α-1946 Target:5′-ACTAGACAAAGTTCACCTGAGCCTAAT-3′ (SEQ ID NO: 956)5′-UGGUAGAAAAACUUUUUGCUGAAGACA-3′ (SEQ ID NO: 1351)3′-ACCAUCUUUUUGAAAAACGACUUCUGU-5′ (SEQ ID NO: 203) HIF-1α-2034 Target:5′-TGGTAGAAAAACTTTTTGCTGAAGACA-3′ (SEQ ID NO: 959)5′-AGCAAAAGACAAUUAUUUUAAUACCCU-3′ (SEQ ID NO: 1352)3′-UCGUUUUCUGUUAAUAAAAUUAUGGGA-5′ (SEQ ID NO: 220) HIF-1α-2730 Target:5′-AGCAAAAGACAATTATTTTAATACCCT-3′ (SEQ ID NO: 976)5′-UGGAUUACCACAGCUGACCAGUUAUGA-3′ (SEQ ID NO: 1353)3′-ACCUAAUGGUGUCGACUGGUCAAUACU-5′ (SEQ ID NO: 223) HIF-1α-2800 Target:5′-TGGATTACCACAGCTGACCAGTTATGA-3′ (SEQ ID NO: 979)5′-AGCUUUGGAUCAAGUUAACUGAGCUUU-3′ (SEQ ID NO: 1354)3′-UCGAAACCUAGUUCAAUUGACUCGAAA-5′ (SEQ ID NO: 249) HIF-1α-2890 Target:5′-AGCTTTGGATCAAGTTAACTGAGCTTT-3′ (SEQ ID NO: 1005)5′-UUCAUUCCUUUUUUUGGACACUGGUGG-3′ (SEQ ID NO: 1355)3′-AAGUAAGGAAAAAAACCUGUGACCACC-5′ (SEQ ID NO: 255) HIF-1α-2925 Target:5′-TTCATTCCTTTTTTTGGACACTGGTGG-3′ (SEQ ID NO: 1011)5′-UUUUUUUGGACACUGGUGGCUCAUUAC-3′ (SEQ ID NO: 1356)3′-AAAAAAACCUGUGACCACCGAGUAAUG-5′ (SEQ ID NO: 256) HIF-1α-2933 Target:5′-TTTTTTTGGACACTGGTGGCTCATTAC-3′ (SEQ ID NO: 1012)5′-AAGCAGUCUAUUUAUAUUUUCUACAUC-3′ (SEQ ID NO: 1357)3′-UUCGUCAGAUAAAUAUAAAAGAUGUAG-5′ (SEQ ID NO: 258) HIF-1α-2963 Target:5′-AAGCAGTCTATTTATATTTTCTACATC-3′ (SEQ ID NO: 1014)5′-GCAGUCUAUUUAUAUUUUCUACAUCUA-3′ (SEQ ID NO: 1358)3′-CGUCAGAUAAAUAUAAAAGAUGUAGAU-5′ (SEQ ID NO: 259) HIF-1α-2965 Target:5′-GCAGTCTATTTATATTTTCTACATCTA-3′ (SEQ ID NO: 1015)5′-CUAUUUAUAUUUUCUACAUCUAAUUUU-3′ (SEQ ID NO: 1359)3′-GAUAAAUAUAAAAGAUGUAGAUUAAAA-5′ (SEQ ID NO: 260) HIF-1α-2970 Target:5′-CTATTTATATTTTCTACATCTAATTTT-3′ (SEQ ID NO: 1016)5′-CUUAAUUUACAUUAAUGCUCUUUUUUA-3′ (SEQ ID NO: 1360)3′-GAAUUAAAUGUAAUUACGAGAAAAAAU-5′ (SEQ ID NO: 271) HIF-1α-3055 Target:5′-CTTAATTTACATTAATGCTCTTTTTTA-3′ (SEQ ID NO: 1027)5′-UCUUUAAUGCUGGAUCACAGACAGCUC-3′ (SEQ ID NO: 1361)3′-AGAAAUUACGACCUAGUGUCUGUCGAG-5′ (SEQ ID NO: 277) HIF-1α-3088 Target:5′-TCTTTAATGCTGGATCACAGACAGCTC-3′ (SEQ ID NO: 1033)5′-AGCUCAUUUUCUCAGUUUUUUGGUAUU-3′ (SEQ ID NO: 1362)3′-UCGAGUAAAAGAGUCAAAAAACCAUAA-5′ (SEQ ID NO: 279) HIF-1α-3110 Target:5′-AGCTCATTTTCTCAGTTTTTTGGTATT-3′ (SEQ ID NO: 1035)5′-CCUUUUUUUUCACAUUUUACAUAAAUA-3′ (SEQ ID NO: 1363)3′-GGAAAAAAAAGUGUAAAAUGUAUUUAU-5′ (SEQ ID NO: 294) HIF-1α-3310 Target:5′-CCTTTTTTTTCACATTTTACATAAATA-3′ (SEQ ID NO: 1050)5′-GCCACAAUUGCACAAUAUAUUUUCUUA-3′ (SEQ ID NO: 1364)3′-CGGUGUUAACGUGUUAUAUAAAAGAAU-5′ (SEQ ID NO: 298) HIF-1α-3364 Target:5′-GCCACAATTGCACAATATATTTTCTTA-3′ (SEQ ID NO: 1054)5′-CACAAUUGCACAAUAUAUUUUCUUAAA-3′ (SEQ ID NO: 1365)3′-GUGUUAACGUGUUAUAUAAAAGAAUUU-5′ (SEQ ID NO: 299) HIF-1α-3366 Target:5′-CACAATTGCACAATATATTTTCTTAAA-3′ (SEQ ID NO: 1055)5′-CACAAUAUAUUUUCUUAAAAAAUACCA-3′ (SEQ ID NO: 1366)3′-GUGUUAUAUAAAAGAAUUUUUUAUGGU-5′ (SEQ ID NO: 301) HIF-1α-3374 Target:5′-CACAATATATTTTCTTAAAAAATACCA-3′ (SEQ ID NO: 1057)5′-UAUAAAACUAGUUUUUAAGAAGAAAUU-3′ (SEQ ID NO: 1367)3′-AUAUUUUGAUCAAAAAUUCUUCUUUAA-5′ (SEQ ID NO: 305) HIF-1α-3430 Target:5′-TATAAAACTAGTTTTTAAGAAGAAATT-3′ (SEQ ID NO: 1061)5′-GAAGAAAUUUUUUUUGGCCUAUGAAAU-3′ (SEQ ID NO: 1368)3′-CUUCUUUAAAAAAAACCGGAUACUUUA-5′ (SEQ ID NO: 307) HIF-1α-3448 Target:5′-GAAGAAATTTTTTTTGGCCTATGAAAT-3′ (SEQ ID NO: 1063)5′-AGAAAUUUUUUUUGGCCUAUGAAAUUG-3′ (SEQ ID NO: 1369)3′-UCUUUAAAAAAAACCGGAUACUUUAAC-5′ (SEQ ID NO: 308) HIF-1α-3450 Target:5′-AGAAATTTTTTTTGGCCTATGAAATTG-3′ (SEQ ID NO: 1064)5′-UAUGUGGCAUUUAUUUGGAUAAAAUUC-3′ (SEQ ID NO: 1370)3′-AUACACCGUAAAUAAACCUAUUUUAAG-5′ (SEQ ID NO: 317) HIF-1α-3598 Target:5′-TATGTGGCATTTATTTGGATAAAATTC-3′ (SEQ ID NO: 1073)5′-AUAAAAUUCUCAAUUCAGAGAAAUCAU-3′ (SEQ ID NO: 1371)3′-UAUUUUAAGAGUUAAGUCUCUUUAGUA-5′ (SEQ ID NO: 327) HIF-1α-3616 Target:5′-ATAAAATTCTCAATTCAGAGAAATCAT-3′ (SEQ ID NO: 1083)5′-AUGUUUCUAUAGUCACUUUGCCAGCUC-3′ (SEQ ID NO: 1372)3′-UACAAAGAUAUCAGUGAAACGGUCGAG-5′ (SEQ ID NO: 329) HIF-1α-3646 Target:5′-ATGTTTCTATAGTCACTTTGCCAGCTC-3′ (SEQ ID NO: 1085)5′-CUCAAAAGAAAACAAUACCCUAUGUAG-3′ (SEQ ID NO: 1373)3′-GAGUUUUCUUUUGUUAUGGGAUACAUC-5′ (SEQ ID NO: 331) HIF-1α-3670 Target:5′-CTCAAAAGAAAACAATACCCTATGTAG-3′ (SEQ ID NO: 1087)5′-UGUUCUGCCUACCCUGUUGGUAUAAAG-3′ (SEQ ID NO: 1374)3′-ACAAGACGGAUGGGACAACCAUAUUUC-5′ (SEQ ID NO: 332) HIF-1α-3743 Target:5′-TGTTCTGCCTACCCTGTTGGTATAAAG-3′ (SEQ ID NO: 1088)5′-CAAGAAAAAAAAAAUCAUGCAUUCUUA-3′ (SEQ ID NO: 1375)3′-GUUCUUUUUUUUUUAGUACGUAAGAAU-5′ (SEQ ID NO: 339) HIF-1α-3791 Target:5′-CAAGAAAAAAAAAATCATGCATTCTTA-3′ (SEQ ID NO: 1095)5′-GAUUUUAUGCACUUUGUCGCUAUUAAC-3′ (SEQ ID NO: 1376)3′-CUAAAAUACGUGAAACAGCGAUAAUUG-5′ (SEQ ID NO: 341) HIF-1α-3861 Target:5′-GATTTTATGCACTTTGTCGCTATTAAC-3′ (SEQ ID NO: 1097)5′-UUUUAUGCACUUUGUCGCUAUUAACAU-3′ (SEQ ID NO: 1377)3′-AAAAUACGUGAAACAGCGAUAAUUGUA-5′ (SEQ ID NO: 342) HIF-1α-3863 Target:5′-TTTTATGCACTTTGTCGCTATTAACAT-3′ (SEQ ID NO: 1098)5′-CUAUUAACAUCCUUUUUUUCAUGUAGA-3′ (SEQ ID NO: 1378)3′-GAUAAUUGUAGGAAAAAAAGUACAUCU-5′ (SEQ ID NO: 350) HIF-1α-3880 Target:5′-CTATTAACATCCTTTTTTTCATGTAGA-3′ (SEQ ID NO: 1106)5′-GUAAUUUUAGAAGCAUUAUUUUAGGAA-3′ (SEQ ID NO: 1379)3′-CAUUAAAAUCUUCGUAAUAAAAUCCUU-5′ (SEQ ID NO: 353) HIF-1α-3920 Target:5′-GTAATTTTAGAAGCATTATTTTAGGAA-3′ (SEQ ID NO: 1109)5′-AAUUUUAGAAGCAUUAUUUUAGGAAUA-3′ (SEQ ID NO: 1380)3′-UUAAAAUCUUCGUAAUAAAAUCCUUAU-5′ (SEQ ID NO: 354) HIF-1α-3922 Target:5′-AATTTTAGAAGCATTATTTTAGGAATA-3′ (SEQ ID NO: 1110)5′-UUUUAGAAGCAUUAUUUUAGGAAUAUA-3′ (SEQ ID NO: 1381)3′-AAAAUCUUCGUAAUAAAAUCCUUAUAU-5′ (SEQ ID NO: 355) HIF-1α-3924 Target:5′-TTTTAGAAGCATTATTTTAGGAATATA-3′ (SEQ ID NO: 1111)5′-AGUAAAUAUCUUGUUUUUUCUAUGUAC-3′ (SEQ ID NO: 1382)3′-UCAUUUAUAGAACAAAAAAGAUACAUG-5′ (SEQ ID NO: 359) HIF-1α-3961 Target:5′-AGTAAATATCTTGTTTTTTCTATGTAC-3′ (SEQ ID NO: 1115)5′-CAUUCCUUUUGCUCUUUGUGGUUGGAU-3′ (SEQ ID NO: 1383)3′-GUAAGGAAAACGAGAAACACCAACCUA-5′ (SEQ ID NO: 364) HIF-1α-4003 Target:5′-CATTCCTTTTGCTCTTTGTGGTTGGAT-3′ (SEQ ID NO: 1120)5′-AUUCCUUUUGCUCUUUGUGGUUGGAUC-3′ (SEQ ID NO: 1384)3′-UAAGGAAAACGAGAAACACCAACCUAG-5′ (SEQ ID NO: 365) HIF-1α-4004 Target:5′-ATTCCTTTTGCTCTTTGTGGTTGGATC-3′ (SEQ ID NO: 1121)5′-UUCCUUUUGCUCUUUGUGGUUGGAUCU-3′ (SEQ ID NO: 1385)3′-AAGGAAAACGAGAAACACCAACCUAGA-5′ (SEQ ID NO: 366) HIF-1α-4005 Target:5′-TTCCTTTTGCTCTTTGTGGTTGGATCT-3′ (SEQ ID NO: 1122)5′-UCCUUUUGCUCUUUGUGGUUGGAUCUA-3′ (SEQ ID NO: 1386)3′-AGGAAAACGAGAAACACCAACCUAGAU-5′ (SEQ ID NO: 367) HIF-1α-4006 Target:5′-TCCTTTTGCTCTTTGTGGTTGGATCTA-3′ (SEQ ID NO: 1123)5′-CCUUUUGCUCUUUGUGGUUGGAUCUAA-3′ (SEQ ID NO: 1387)3′-GGAAAACGAGAAACACCAACCUAGAUU-5′ (SEQ ID NO: 368) HIF-1α-4007 Target:5′-CCTTTTGCTCTTTGTGGTTGGATCTAA-3′ (SEQ ID NO: 1124)5′-CUUUUGCUCUUUGUGGUUGGAUCUAAC-3′ (SEQ ID NO: 1388)3′-GAAAACGAGAAACACCAACCUAGAUUG-5′ (SEQ ID NO: 369) HIF-1α-4008 Target:5′-CTTTTGCTCTTTGTGGTTGGATCTAAC-3′ (SEQ ID NO: 1125)5′-UUUUGCUCUUUGUGGUUGGAUCUAACA-3′ (SEQ ID NO: 1389)3′-AAAACGAGAAACACCAACCUAGAUUGU-5′ (SEQ ID NO: 370) HIF-1α-4009 Target:5′-TTTTGCTCTTTGTGGTTGGATCTAACA-3′ (SEQ ID NO: 1126)5′-UUUGCUCUUUGUGGUUGGAUCUAACAC-3′ (SEQ ID NO: 1390)3′-AAACGAGAAACACCAACCUAGAUUGUG-5′ (SEQ ID NO: 371) HIF-1α-4010 Target:5′-TTTGCTCTTTGTGGTTGGATCTAACAC-3′ (SEQ ID NO: 1127)5′-GCAGAAACCUACUGCAGGGUGAAGAAU-3′ (SEQ ID NO: 1391)3′-CGUCUUUGGAUGACGUCCCACUUCUUA-5′ (SEQ ID NO: 232) HIF-1α-2856 Target:5′-GCAGAAACCTACTGCAGGGTGAAGAAT-3′ (SEQ ID NO: 988)5′-CAAAUAUUGAAAUUCCUUUAGAUAGCA-3′ (SEQ ID NO: 1392)3′-GUUUAUAACUUUAAGGAAAUCUAUCGU-5′ (SEQ ID NO: 102) HIF-1α-1122 Target:5′-CAAATATTGAAATTCCTTTAGATAGCA-3′ (SEQ ID NO: 858)5′-AGAAACCUACUGCAGGGUGAAGAAUUA-3′ (SEQ ID NO: 1393)3′-UCUUUGGAUGACGUCCCACUUCUUAAU-5′ (SEQ ID NO: 233) HIF-1α-2858 Target:5′-AGAAACCTACTGCAGGGTGAAGAATTA-3′ (SEQ ID NO: 989)5′-ACCUACUGCAGGGUGAAGAAUUACUCA-3′ (SEQ ID NO: 1394)3′-UGGAUGACGUCCCACUUCUUAAUGAGU-5′ (SEQ ID NO: 235) HIF-1α-2862 Target:5′-ACCTACTGCAGGGTGAAGAATTACTCA-3′ (SEQ ID NO: 991)5′-CCUUUUUUUUCACAUUUUACAUAAAUA-3′ (SEQ ID NO: 1395)3′-GGAAAAAAAAGUGUAAAAUGUAUUUAU-5′ (SEQ ID NO: 294) HIF-1α-3310 Target:5′-CCTTTTTTTTCACATTTTACATAAATA-3′ (SEQ ID NO: 1050)5′-ACUCAAGCAACUGUCAUAUAUAACACC-3′ (SEQ ID NO: 1396)3′-UGAGUUCGUUGACAGUAUAUAUUGUGG-5′ (SEQ ID NO: 166) HIF-1α-1385 Target:5′-ACTCAAGCAACTGTCATATATAACACC-3′ (SEQ ID NO: 922)5′-AGCUUUGGAUCAAGUUAACUGAGCUUU-3′ (SEQ ID NO: 1397)3′-UCGAAACCUAGUUCAAUUGACUCGAAA-5′ (SEQ ID NO: 249) HIF-1α-2890 Target:5′-AGCTTTGGATCAAGTTAACTGAGCTTT-3′ (SEQ ID NO: 1005)5′-AGCGAAGCUUUUUUCUCAGAAUGAAGU-3′ (SEQ ID NO: 1398)3′-UCGCUUCGAAAAAAGAGUCUUACUUCA-5′ (SEQ ID NO: 79) HIF-1α-921 Target:5′-AGCGAAGCTTTTTTCTCAGAATGAAGT-3′ (SEQ ID NO: 835)5′-UGCUCUUUGUGGUUGGAUCUAACACUA-3′ (SEQ ID NO: 1399)3′-ACGAGAAACACCAACCUAGAUUGUGAU-5′ (SEQ ID NO: 372) HIF-1α-4012 Target:5′-TGCTCTTTGTGGTTGGATCTAACACTA-3′ (SEQ ID NO: 1128)5′-AAGCAUUAUUUUAGGAAUAUAUAGUUG-3′ (SEQ ID NO: 1400)3′-UUCGUAAUAAAAUCCUUAUAUAUCAAC-5′ (SEQ ID NO: 358) HIF-1α-3930 Target:5′-AAGCATTATTTTAGGAATATATAGTTG-3′ (SEQ ID NO: 1114)5′-GAUUACCACAGCUGACCAGUUAUGAUU-3′ (SEQ ID NO: 1401)3′-CUAAUGGUGUCGACUGGUCAAUACUAA-5′ (SEQ ID NO: 224) HIF-1α-2802 Target:5′-GATTACCACAGCTGACCAGTTATGATT-3′ (SEQ ID NO: 980)5′-UGAAACUCAAGCAACUGUCAUAUAUAA-3′ (SEQ ID NO: 1402)3′-ACUUUGAGUUCGUUGACAGUAUAUAUU-5′ (SEQ ID NO: 164) HIF-1α-1381 Target:5′-TGAAACTCAAGCAACTGTCATATATAA-3′ (SEQ ID NO: 920)5′-AGUGGAUUACCACAGCUGACCAGUUAU-3′ (SEQ ID NO: 1403)3′-UCACCUAAUGGUGUCGACUGGUCAAUA-5′ (SEQ ID NO: 222) HIF-1α-2798 Target:5′-AGTGGATTACCACAGCTGACCAGTTAT-3′ (SEQ ID NO: 978)5′-AAGCAGUCUAUUUAUAUUUUCUACAUC-3′ (SEQ ID NO: 1404)3′-UUCGUCAGAUAAAUAUAAAAGAUGUAG-5′ (SEQ ID NO: 258) HIF-1α-2963 Target:5′-AAGCAGTCTATTTATATTTTCTACATC-3′ (SEQ ID NO: 1014)5′-UUGAUUUUCUCCCUUCAACAAACAGAA-3′ (SEQ ID NO: 1405)3′-AACUAAAAGAGGGAAGUUGUUUGUCUU-5′ (SEQ ID NO: 179) HIF-1α-1478 Target:5′-TTGATTTTCTCCCTTCAACAAACAGAA-3′ (SEQ ID NO: 935)5′-AAUUACUCAGAGCUUUGGAUCAAGUUA-3′ (SEQ ID NO: 1406)3′-UUAAUGAGUCUCGAAACCUAGUUCAAU-5′ (SEQ ID NO: 244) HIF-1α-2880 Target:5′-AATTACTCAGAGCTTTGGATCAAGTTA-3′ (SEQ ID NO: 1000)5′-UUGAGUAAUUUUAGAAGCAUUAUUUUA-3′ (SEQ ID NO: 1407)3′-AACUCAUUAAAAUCUUCGUAAUAAAAU-5′ (SEQ ID NO: 351) HIF-1α-3916 Target:5′-TTGAGTAATTTTAGAAGCATTATTTTA-3′ (SEQ ID NO: 1107)5′-UCUAAUUUUAGAAGCCUGGCUACAAUA-3′ (SEQ ID NO: 1408)3′-AGAUUAAAAUCUUCGGACCGAUGUUAU-5′ (SEQ ID NO: 262) HIF-1α-2988 Target:5′-TCTAATTTTAGAAGCCTGGCTACAATA-3′ (SEQ ID NO: 1018)5′-UUAUGCACUUUGUCGCUAUUAACAUCC-3′ (SEQ ID NO: 1409)3′-AAUACGUGAAACAGCGAUAAUUGUAGG-5′ (SEQ ID NO: 343) HIF-1α-3865 Target:5′-TTATGCACTTTGTCGCTATTAACATCC-3′ (SEQ ID NO: 1099)5′-GGCAGCAGAAACCUACUGCAGGGUGAA-3′ (SEQ ID NO: 1410)3′-CCGUCGUCUUUGGAUGACGUCCCACUU-5′ (SEQ ID NO: 230) HIF-1α-2852 Target:5′-GGCAGCAGAAACCTACTGCAGGGTGAA-3′ (SEQ ID NO: 986)5′-GAAGAAUUACUCAGAGCUUUGGAUCAA-3′ (SEQ ID NO: 1411)3′-CUUCUUAAUGAGUCUCGAAACCUAGUU-5′ (SEQ ID NO: 242) HIF-1α-2876 Target:5′-GAAGAATTACTCAGAGCTTTGGATCAA-3′ (SEQ ID NO: 998)5′-GUGAAGAAUUACUCAGAGCUUUGGAUC-3′ (SEQ ID NO: 1412)3′-CACUUCUUAAUGAGUCUCGAAACCUAG-5′ (SEQ ID NO: 241) HIF-1α-2874 Target:5′-GTGAAGAATTACTCAGAGCTTTGGATC-3′ (SEQ ID NO: 997)5′-UUACUCAGAGCUUUGGAUCAAGUUAAC-3′ (SEQ ID NO: 1413)3′-AAUGAGUCUCGAAACCUAGUUCAAUUG-5′ (SEQ ID NO: 245) HIF-1α-2882 Target:5′-TTACTCAGAGCTTTGGATCAAGTTAAC-3′ (SEQ ID NO: 1001)

Within Tables 2-4 and 6-7 above, underlined residues indicate2′-O-methyl residues, UPPER CASE indicates ribonucleotides, and lowercase denotes deoxyribonucleotides. The DsiRNA agents of Tables 2-4 aboveare 25/27mer agents possessing a blunt end. The structures and/ormodification patterning of the agents of Tables 2-4 and 6-7 above can bereadily adapted to the above generic sequence structures, e.g., the 3′overhang of the second strand can be extended or contracted,2′-O-methylation of the second strand can be expanded towards the 5′ endof the second strand, optionally at alternating sites, etc. Such furthermodifications are optional, as 25/27mer DsiRNAs with such modificationscan also be readily designed from the above DsiRNA agents and are alsoexpected to be functional inhibitors of HIF-1α expression. Similarly,the 27mer “blunt/fray” and “blunt/blunt” DsiRNA structures and/ormodification patterns of the agents of Tables 6-7 above can also bereadily adapted to the above generic sequence structures, e.g., forapplication of modification patterning of the antisense strand to suchstructures and/or adaptation of such sequences to the above genericstructures.

In certain embodiments, 27mer DsiRNAs possessing independent strandlengths each of 27 nucleotides are designed and synthesized fortargeting of the same sites within the HIF-1α transcript as theasymmetric “25/27” structures shown in Tables 2-4 herein. Exemplary“27/27” DsiRNAs are optionally designed with a “blunt/fray” structure asshown for the DsiRNAs of Table 6 above, or with a “blunt/blunt”structure as shown for the DsiRNAs of Tables 7 above.

In certain embodiments, the dsRNA agents of the invention require, e.g.,at least 19, at least 20, at least 21, at least 22, at least 23, atleast 24, at least 25 or at least 26 residues of the first strand to becomplementary to corresponding residues of the second strand. In certainrelated embodiments, these first strand residues complementary tocorresponding residues of the second strand are optionally consecutiveresidues.

By definition, “sufficiently complementary” (contrasted with, e.g.,“100% complementary”) allows for one or more mismatches to exist betweena dsRNA of the invention and the target RNA or cDNA sequence (e.g.,HIF-1α mRNA), provided that the dsRNA possesses complementaritysufficient to trigger the destruction of the target RNA by the RNAimachinery (e.g., the RISC complex) or process. In certain embodiments, a“sufficiently complementary” dsRNA of the invention can harbor one, two,three or even four or more mismatches between the dsRNA sequence and thetarget RNA or cDNA sequence (e.g., in certain such embodiments, theantisense strand of the dsRNA harbors one, two, three, four, five oreven six or more mismatches when aligned with the target RNA or cDNAsequence). Additional consideration of the preferred location of suchmismatches within certain dsRNAs of the instant invention is consideredin greater detail below.

As used herein “DsiRNAmm” refers to a DisRNA having a “mismatch tolerantregion” containing one, two, three or four mismatched base pairs of theduplex formed by the sense and antisense strands of the DsiRNA, wheresuch mismatches are positioned within the DsiRNA at a location(s) lyingbetween (and thus not including) the two terminal base pairs of eitherend of the DsiRNA. The mismatched base pairs are located within a“mismatch-tolerant region” which is defined herein with respect to thelocation of the projected Ago2 cut site of the corresponding targetnucleic acid. The mismatch tolerant region is located “upstream of” theprojected Ago2 cut site of the target strand. “Upstream” in this contextwill be understood as the 5′-most portion of the DsiRNAmm duplex, where5′ refers to the orientation of the sense strand of the DsiRNA duplex.Therefore, the mismatch tolerant region is upstream of the base on thesense (passenger) strand that corresponds to the projected Ago2 cut siteof the target nucleic acid (see FIG. 1); alternatively, when referringto the antisense (guide) strand of the DsiRNAmm, the mismatch tolerantregion can also be described as positioned downstream of the base thatis complementary to the projected Ago2 cut site of the target nucleicacid, that is, the 3′-most portion of the antisense strand of theDsiRNAmm (where position 1 of the antisense strand is the 5′ terminalnucleotide of the antisense strand, see FIG. 1).

In one embodiment, for example with numbering as depicted in FIG. 1, themismatch tolerant region is positioned between and including base pairs3-9 when numbered from the nucleotide starting at the 5′ end of thesense strand of the duplex. Therefore, a DsiRNAmm of the inventionpossesses a single mismatched base pair at any one of positions 3, 4, 5,6, 7, 8 or 9 of the sense strand of a right-hand extended DsiRNA (whereposition 1 is the 5′ terminal nucleotide of the sense strand andposition 9 is the nucleotide residue of the sense strand that isimmediately 5′ of the projected Ago2 cut site of the target HIF-1α RNAsequence corresponding to the sense strand sequence). In certainembodiments, for a DsiRNAmm that possesses a mismatched base pairnucleotide at any of positions 3, 4, 5, 6, 7, 8 or 9 of the sensestrand, the corresponding mismatched base pair nucleotide of theantisense strand not only forms a mismatched base pair with the DsiRNAmmsense strand sequence, but also forms a mismatched base pair with aDsiRNAmm target HIF-1α RNA sequence (thus, complementarity between theantisense strand sequence and the sense strand sequence is disrupted atthe mismatched base pair within the DsiRNAmm, and complementarity issimilarly disrupted between the antisense strand sequence of theDsiRNAmm and the target HIF-1α RNA sequence). In alternativeembodiments, the mismatch base pair nucleotide of the antisense strandof a DsiRNAmm only form a mismatched base pair with a correspondingnucleotide of the sense strand sequence of the DsiRNAmm, yet base pairswith its corresponding target HIF-1α RNA sequence nucleotide (thus,complementarity between the antisense strand sequence and the sensestrand sequence is disrupted at the mismatched base pair within theDsiRNAmm, yet complementarity is maintained between the antisense strandsequence of the DsiRNAmm and the target HIF-1αRNA sequence).

A DsiRNAmm of the invention that possesses a single mismatched base pairwithin the mismatch-tolerant region (mismatch region) as described above(e.g., a DsiRNAmm harboring a mismatched nucleotide residue at any oneof positions 3, 4, 5, 6, 7, 8 or 9 of the sense strand) can furtherinclude one, two or even three additional mismatched base pairs. Inpreferred embodiments, these one, two or three additional mismatchedbase pairs of the DsiRNAmm occur at position(s) 3, 4, 5, 6, 7, 8 and/or9 of the sense strand (and at corresponding residues of the antisensestrand). In one embodiment where one additional mismatched base pair ispresent within a DsiRNAmm, the two mismatched base pairs of the sensestrand can occur, e.g., at nucleotides of both position 4 and position 6of the sense strand (with mismatch also occurring at correspondingnucleotide residues of the antisense strand).

In DsiRNAmm agents possessing two mismatched base pairs, mismatches canoccur consecutively (e.g., at consecutive positions along the sensestrand nucleotide sequence). Alternatively, nucleotides of the sensestrand that form mismatched base pairs with the antisense strandsequence can be interspersed by nucleotides that base pair with theantisense strand sequence (e.g., for a DsiRNAmm possessing mismatchednucleotides at positions 3 and 6, but not at positions 4 and 5, themismatched residues of sense strand positions 3 and 6 are interspersedby two nucleotides that form matched base pairs with correspondingresidues of the antisense strand). For example, two residues of thesense strand (located within the mismatch-tolerant region of the sensestrand) that form mismatched base pairs with the corresponding antisensestrand sequence can occur with zero, one, two, three, four or fivematched base pairs located between these mismatched base pairs.

For certain DsiRNAmm agents possessing three mismatched base pairs,mismatches can occur consecutively (e.g., in a triplet along the sensestrand nucleotide sequence). Alternatively, nucleotides of the sensestrand that form mismatched base pairs with the antisense strandsequence can be interspersed by nucleotides that form matched base pairswith the antisense strand sequence (e.g., for a DsiRNAmm possessingmismatched nucleotides at positions 3, 4 and 8, but not at positions 5,6 and 7, the mismatched residues of sense strand positions 3 and 4 areadjacent to one another, while the mismatched residues of sense strandpositions 4 and 8 are interspersed by three nucleotides that formmatched base pairs with corresponding residues of the antisense strand).For example, three residues of the sense strand (located within themismatch-tolerant region of the sense strand) that form mismatched basepairs with the corresponding antisense strand sequence can occur withzero, one, two, three or four matched base pairs located between any twoof these mismatched base pairs.

For certain DsiRNAmm agents possessing four mismatched base pairs,mismatches can occur consecutively (e.g., in a quadruplet along thesense strand nucleotide sequence). Alternatively, nucleotides of thesense strand that form mismatched base pairs with the antisense strandsequence can be interspersed by nucleotides that form matched base pairswith the antisense strand sequence (e.g., for a DsiRNAmm possessingmismatched nucleotides at positions 3, 5, 7 and 8, but not at positions4 and 6, the mismatched residues of sense strand positions 7 and 8 areadjacent to one another, while the mismatched residues of sense strandpositions 3 and 5 are interspersed by one nucleotide that forms amatched base pair with the corresponding residue of the antisensestrand—similarly, the mismatched residues of sense strand positions 5and 7 are also interspersed by one nucleotide that forms a matched basepair with the corresponding residue of the antisense strand). Forexample, four residues of the sense strand (located within themismatch-tolerant region of the sense strand) that form mismatched basepairs with the corresponding antisense strand sequence can occur withzero, one, two or three matched base pairs located between any two ofthese mismatched base pairs.

In another embodiment, for example with numbering also as depicted inFIG. 1, a DsiRNAmm of the invention comprises a mismatch tolerant regionwhich possesses a single mismatched base pair nucleotide at any one ofpositions 17, 18, 19, 20, 21, 22 or 23 of the antisense strand of theDsiRNA (where position 1 is the 5′ terminal nucleotide of the antisensestrand and position 17 is the nucleotide residue of the antisense strandthat is immediately 3′ (downstream) in the antisense strand of theprojected Ago2 cut site of the target HIF-1α RNA sequence sufficientlycomplementary to the antisense strand sequence). In certain embodiments,for a DsiRNAmm that possesses a mismatched base pair nucleotide at anyof positions 17, 18, 19, 20, 21, 22 or 23 of the antisense strand withrespect to the sense strand of the DsiRNAmm, the mismatched base pairnucleotide of the antisense strand not only forms a mismatched base pairwith the DsiRNAmm sense strand sequence, but also forms a mismatchedbase pair with a DsiRNAmm target HIF-1α RNA sequence (thus,complementarity between the antisense strand sequence and the sensestrand sequence is disrupted at the mismatched base pair within theDsiRNAmm, and complementarity is similarly disrupted between theantisense strand sequence of the DsiRNAmm and the target HIF-1α RNAsequence). In alternative embodiments, the mismatch base pair nucleotideof the antisense strand of a DsiRNAmm only forms a mismatched base pairwith a corresponding nucleotide of the sense strand sequence of theDsiRNAmm, yet base pairs with its corresponding target HIF-1α RNAsequence nucleotide (thus, complementarity between the antisense strandsequence and the sense strand sequence is disrupted at the mismatchedbase pair within the DsiRNAmm, yet complementarity is maintained betweenthe antisense strand sequence of the DsiRNAmm and the target HIF-1αRNAsequence).

A DsiRNAmm of the invention that possesses a single mismatched base pairwithin the mismatch-tolerant region as described above (e.g., a DsiRNAmmharboring a mismatched nucleotide residue at positions 17, 18, 19, 20,21, 22 or 23 of the antisense strand) can further include one, two oreven three additional mismatched base pairs. In preferred embodiments,these one, two or three additional mismatched base pairs of the DsiRNAmmoccur at position(s) 17, 18, 19, 20, 21, 22 and/or 23 of the antisensestrand (and at corresponding residues of the sense strand). In oneembodiment where one additional mismatched base pair is present within aDsiRNAmm, the two mismatched base pairs of the antisense strand canoccur, e.g., at nucleotides of both position 18 and position 20 of theantisense strand (with mismatch also occurring at correspondingnucleotide residues of the sense strand).

In DsiRNAmm agents possessing two mismatched base pairs, mismatches canoccur consecutively (e.g., at consecutive positions along the antisensestrand nucleotide sequence). Alternatively, nucleotides of the antisensestrand that form mismatched base pairs with the sense strand sequencecan be interspersed by nucleotides that base pair with the sense strandsequence (e.g., for a DsiRNAmm possessing mismatched nucleotides atpositions 17 and 20, but not at positions 18 and 19, the mismatchedresidues of antisense strand positions 17 and 20 are interspersed by twonucleotides that form matched base pairs with corresponding residues ofthe sense strand). For example, two residues of the antisense strand(located within the mismatch-tolerant region of the sense strand) thatform mismatched base pairs with the corresponding sense strand sequencecan occur with zero, one, two, three, four, five, six or seven matchedbase pairs located between these mismatched base pairs.

For certain DsiRNAmm agents possessing three mismatched base pairs,mismatches can occur consecutively (e.g., in a triplet along theantisense strand nucleotide sequence). Alternatively, nucleotides of theantisense strand that form mismatched base pairs with the sense strandsequence can be interspersed by nucleotides that form matched base pairswith the sense strand sequence (e.g., for a DsiRNAmm possessingmismatched nucleotides at positions 17, 18 and 22, but not at positions19, 20 and 21, the mismatched residues of antisense strand positions 17and 18 are adjacent to one another, while the mismatched residues ofantisense strand positions 18 and 122 are interspersed by threenucleotides that form matched base pairs with corresponding residues ofthe sense strand). For example, three residues of the antisense strand(located within the mismatch-tolerant region of the antisense strand)that form mismatched base pairs with the corresponding sense strandsequence can occur with zero, one, two, three, four, five or six matchedbase pairs located between any two of these mismatched base pairs.

For certain DsiRNAmm agents possessing four mismatched base pairs,mismatches can occur consecutively (e.g., in a quadruplet along theantisense strand nucleotide sequence). Alternatively, nucleotides of theantisense strand that form mismatched base pairs with the sense strandsequence can be interspersed by nucleotides that form matched base pairswith the sense strand sequence (e.g., for a DsiRNAmm possessingmismatched nucleotides at positions 18, 20, 22 and 23, but not atpositions 19 and 21, the mismatched residues of antisense strandpositions 22 and 23 are adjacent to one another, while the mismatchedresidues of antisense strand positions 18 and 20 are interspersed by onenucleotide that forms a matched base pair with the corresponding residueof the sense strand—similarly, the mismatched residues of antisensestrand positions 20 and 22 are also interspersed by one nucleotide thatforms a matched base pair with the corresponding residue of the sensestrand). For example, four residues of the antisense strand (locatedwithin the mismatch-tolerant region of the antisense strand) that formmismatched base pairs with the corresponding sense strand sequence canoccur with zero, one, two, three, four or five matched base pairslocated between any two of these mismatched base pairs.

For reasons of clarity, the location(s) of mismatched nucleotideresidues within the above DsiRNAmm agents are numbered in reference tothe 5′ terminal residue of either sense or antisense strands of theDsiRNAmm. The numbering of positions located within themismatch-tolerant region (mismatch region) of the antisense strand canshift with variations in the proximity of the 5′ terminus of the senseor antisense strand to the projected Ago2 cleavage site. Thus, thelocation(s) of preferred mismatch sites within either antisense strandor sense strand can also be identified as the permissible proximity ofsuch mismatches to the projected Ago2 cut site. Accordingly, in onepreferred embodiment, the position of a mismatch nucleotide of the sensestrand of a DsiRNAmm is the nucleotide residue of the sense strand thatis located immediately 5′ (upstream) of the projected Ago2 cleavage siteof the corresponding target HIF-1α RNA sequence. In other preferredembodiments, a mismatch nucleotide of the sense strand of a DsiRNAmm ispositioned at the nucleotide residue of the sense strand that is locatedtwo nucleotides 5′ (upstream) of the projected Ago2 cleavage site, threenucleotides 5′ (upstream) of the projected Ago2 cleavage site, fournucleotides 5′ (upstream) of the projected Ago2 cleavage site, fivenucleotides 5′ (upstream) of the projected Ago2 cleavage site, sixnucleotides 5′ (upstream) of the projected Ago2 cleavage site, sevennucleotides 5′ (upstream) of the projected Ago2 cleavage site, eightnucleotides 5′ (upstream) of the projected Ago2 cleavage site, or ninenucleotides 5′ (upstream) of the projected Ago2 cleavage site.

Exemplary single mismatch-containing 25/27mer DsiRNAs (DsiRNAmm) includethe following structures (such mismatch-containing structures may alsobe incorporated into other exemplary DsiRNA structures shown herein).

wherein “X”=RNA, “D”=DNA and “M”=Nucleic acid residues (RNA, DNA ornon-natural or modified nucleic acids) that do not base pair (hydrogenbond) with corresponding “M” residues of otherwise complementary strandwhen strands are annealed. Any of the residues of such agents canoptionally be 2′-O-methyl RNA monomers—alternating positioning of2′-O-methyl RNA monomers that commences from the 3′-terminal residue ofthe bottom (second) strand, as shown above, can also be used in theabove DsiRNAmm agents. For the above mismatch structures, the top strandis the sense strand, and the bottom strand is the antisense strand.

In certain embodiments, a DsiRNA of the invention can contain mismatchesthat exist in reference to the target HIF-1α RNA sequence yet do notnecessarily exist as mismatched base pairs within the two strands of theDsiRNA—thus, a DsiRNA can possess perfect complementarity between firstand second strands of a DsiRNA, yet still possess mismatched residues inreference to a target HIF-1α RNA (which, in certain embodiments, may beadvantageous in promoting efficacy and/or potency and/or duration ofeffect). In certain embodiments, where mismatches occur betweenantisense strand and target HIF-1α RNA sequence, the position of amismatch is located within the antisense strand at a position(s) thatcorresponds to a sequence of the sense strand located 5′ of theprojected Ago2 cut site of the target region—e.g., antisense strandresidue(s) positioned within the antisense strand to the 3′ of theantisense residue which is complementary to the projected Ago2 cut siteof the target sequence.

Exemplary 25/27mer DsiRNAs that harbor a single mismatched residue inreference to target sequences include the following structures.

Target RNA Sequence: 5′-...AXXXXXXXXXXXXXXXXXXXX...-3′ DsiRNAmm SenseStrand: 5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ DsiRNAmm Antisense Strand:3′-EXXXXXXXXXXXXXXXXXXXXXXXXXX-5′ Target RNA Sequence:5′-...XAXXXXXXXXXXXXXXXXXXX...-3′ DsiRNAmm Sense Strand:5′-XXXXXXXXXXXXXXXXXXXXXXXDD-3′ DsiRNAmm Antisense Strand:3′-XEXXXXXXXXXXXXXXXXXXXXXXXXX-5′ Target RNA Sequence:5′-...AXXXXXXXXXXXXXXXXXX...-3′ DsiRNAmm Sense Strand:5′-BXXXXXXXXXXXXXXXXXXXXXXDD-3′ DsiRNAmm Antisense Strand:3′-XXEXXXXXXXXXXXXXXXXXXXXXXXX-5′ Target RNA Sequence:5′-...XAXXXXXXXXXXXXXXXXX...-3′ DsiRNAmm Sense Strand:5′-XBXXXXXXXXXXXXXXXXXXXXXDD-3′ DsiRNAmm Antisense Strand:3′-XXXEXXXXXXXXXXXXXXXXXXXXXXX-5′ Target RNA Sequence:5′-...XXAXXXXXXXXXXXXXXXX...-3′ DsiRNAmm Sense Strand:5′-XXBXXXXXXXXXXXXXXXXXXXXDD-3′ DsiRNAmm Antisense Strand:3′-XXXXEXXXXXXXXXXXXXXXXXXXXXX-5′ Target RNA Sequence:5′-...XXXAXXXXXXXXXXXXXXX...-3′ DsiRNAmm Sense Strand:5′-XXXBXXXXXXXXXXXXXXXXXXXDD-3′ DsiRNAmm Antisense Strand:3′-XXXXXEXXXXXXXXXXXXXXXXXXXXX-5′ Target RNA Sequence:5′-...XXXXAXXXXXXXXXXXXXX...-3′ DsiRNAmm Sense Strand:5′-XXXXBXXXXXXXXXXXXXXXXXXDD-3′ DsiRNAmm Antisense Strand:3′-XXXXXXEXXXXXXXXXXXXXXXXXXXX-5′ Target RNA Sequence:5′-...XXXXXAXXXXXXXXXXXXX...-3′ DsiRNAmm Sense Strand:5′-XXXXXBXXXXXXXXXXXXXXXXXDD-3′ DsiRNAmm Antisense Strand:3′-XXXXXXXEXXXXXXXXXXXXXXXXXXX-5′ Target RNA Sequence:5′-...XXXXXXAXXXXXXXXXXXX...-3′ DsiRNAmm Sense Strand:5′-XXXXXXBXXXXXXXXXXXXXXXXDD-3′ DsiRNAmm Antisense Strand:3′-XXXXXXXXEXXXXXXXXXXXXXXXXXX-5′ Target RNA Sequence:5′-...XXXXXXXAXXXXXXXXXXX...-3′ DsiRNAmm Sense Strand:5′-XXXXXXXBXXXXXXXXXXXXXXXDD-3′ DsiRNAmm Antisense Strand:3′-XXXXXXXXXEXXXXXXXXXXXXXXXXX-5′ Target RNA Sequence:5′-...XXXXXXXXAXXXXXXXXXX...-3′ DsiRNAmm Sense Strand:5′-XXXXXXXXBXXXXXXXXXXXXXXDD-3′ DsiRNAmm Antisense Strand:3′-XXXXXXXXXXEXXXXXXXXXXXXXXXX-5′wherein “X”=RNA, “D”=DNA and “E”=Nucleic acid residues (RNA, DNA ornon-natural or modified nucleic acids) that do not base pair (hydrogenbond) with corresponding “A” RNA residues of otherwise complementary(target) strand when strands are annealed, yet optionally do base pairwith corresponding “B” residues (“B” residues are also RNA, DNA ornon-natural or modified nucleic acids). Any of the residues of suchagents can optionally be 2′-O-methyl RNA monomers—alternatingpositioning of 2′-O-methyl RNA monomers that commences from the3′-terminal residue of the bottom (second) strand, as shown above, canalso be used in the above DsiRNA agents.

In certain embodiments, the guide strand of a dsRNA of the inventionthat is sufficiently complementary to a target RNA (e.g., mRNA) along atleast 19 nucleotides of the target gene sequence to reduce target geneexpression is not perfectly complementary to the at least 19 nucleotidelong target gene sequence. Rather, it is appreciated that the guidestrand of a dsRNA of the invention that is sufficiently complementary toa target mRNA along at least 19 nucleotides of a target RNA sequence toreduce target gene expression can have one, two, three, or even four ormore nucleotides that are mismatched with the 19 nucleotide or longertarget strand sequence. Thus, for a 19 nucleotide target RNA sequence,the guide strand of a dsRNA of the invention can be sufficientlycomplementary to the target RNA sequence to reduce target gene levelswhile possessing, e.g., only 15/19, 16/19, 17/19 or 18/19 matchednucleotide residues between guide strand and target RNA sequence.

In addition to the above-exemplified structures, dsRNAs of the inventioncan also possess one, two or three additional residues that form furthermismatches with the target HIF-1α RNA sequence. Such mismatches can beconsecutive, or can be interspersed by nucleotides that form matchedbase pairs with the target HIF-1α RNA sequence. Where interspersed bynucleotides that form matched base pairs, mismatched residues can bespaced apart from each other within a single strand at an interval ofone, two, three, four, five, six, seven or even eight base pairednucleotides between such mismatch-forming residues.

As for the above-described DsiRNAmm agents, a preferred location withindsRNAs (e.g., DsiRNAs) for antisense strand nucleotides that formmismatched base pairs with target HIF-1αRNA sequence (yet may or may notform mismatches with corresponding sense strand nucleotides) is withinthe antisense strand region that is located 3′ (downstream) of theantisense strand sequence which is complementary to the projected Ago2cut site of the DsiRNA (e.g., in FIG. 1, the region of the antisensestrand which is 3′ of the projected Ago2 cut site is preferred formismatch-forming residues and happens to be located at positions 17-23of the antisense strand for the 25/27mer agent shown in FIG. 1). Thus,in one embodiment, the position of a mismatch nucleotide (in relation tothe target HIF-1α RNA sequence) of the antisense strand of a DsiRNAmm isthe nucleotide residue of the antisense strand that is locatedimmediately 3′ (downstream) within the antisense strand sequence of theprojected Ago2 cleavage site of the corresponding target HIF-1α RNAsequence. In other preferred embodiments, a mismatch nucleotide of theantisense strand of a DsiRNAmm (in relation to the target HIF-1α RNAsequence) is positioned at the nucleotide residue of the antisensestrand that is located two nucleotides 3′ (downstream) of thecorresponding projected Ago2 cleavage site, three nucleotides 3′(downstream) of the corresponding projected Ago2 cleavage site, fournucleotides 3′ (downstream) of the corresponding projected Ago2 cleavagesite, five nucleotides 3′ (downstream) of the corresponding projectedAgo2 cleavage site, six nucleotides 3′ (downstream) of the projectedAgo2 cleavage site, seven nucleotides 3′ (downstream) of the projectedAgo2 cleavage site, eight nucleotides 3′ (downstream) of the projectedAgo2 cleavage site, or nine nucleotides 3′ (downstream) of the projectedAgo2 cleavage site.

In dsRNA agents possessing two mismatch-forming nucleotides of theantisense strand (where mismatch-forming nucleotides are mismatchforming in relation to target HIF-1α RNA sequence), mismatches can occurconsecutively (e.g., at consecutive positions along the antisense strandnucleotide sequence). Alternatively, nucleotides of the antisense strandthat form mismatched base pairs with the target HIF-1α RNA sequence canbe interspersed by nucleotides that base pair with the target HIF-1α RNAsequence (e.g., for a DsiRNA possessing mismatch-forming nucleotides atpositions 17 and 20 (starting from the 5′ terminus (position 1) of theantisense strand of the 25/27mer agent shown in FIG. 1), but not atpositions 18 and 19, the mismatched residues of sense strand positions17 and 20 are interspersed by two nucleotides that form matched basepairs with corresponding residues of the target HIF-1α RNA sequence).For example, two residues of the antisense strand (located within themismatch-tolerant region of the antisense strand) that form mismatchedbase pairs with the corresponding target HIF-1α RNA sequence can occurwith zero, one, two, three, four or five matched base pairs (withrespect to target HIF-1α RNA sequence) located between thesemismatch-forming base pairs.

For certain dsRNAs possessing three mismatch-forming base pairs(mismatch-forming with respect to target HIF-1α RNA sequence),mismatch-forming nucleotides can occur consecutively (e.g., in a tripletalong the antisense strand nucleotide sequence). Alternatively,nucleotides of the antisense strand that form mismatched base pairs withthe target HIF-1α RNA sequence can be interspersed by nucleotides thatform matched base pairs with the target HIF-1αRNA sequence (e.g., for aDsiRNA possessing mismatched nucleotides at positions 17, 18 and 22, butnot at positions 19, 20 and 21, the mismatch-forming residues ofantisense strand positions 17 and 18 are adjacent to one another, whilethe mismatch-forming residues of antisense strand positions 18 and 22are interspersed by three nucleotides that form matched base pairs withcorresponding residues of the target HIF-1α RNA). For example, threeresidues of the antisense strand (located within the mismatch-tolerantregion of the antisense strand) that form mismatched base pairs with thecorresponding target HIF-1α RNA sequence can occur with zero, one, two,three or four matched base pairs located between any two of thesemismatch-forming base pairs.

For certain dsRNAs possessing four mismatch-forming base pairs(mismatch-forming with respect to target HIF-1α RNA sequence),mismatch-forming nucleotides can occur consecutively (e.g., in aquadruplet along the sense strand nucleotide sequence). Alternatively,nucleotides of the antisense strand that form mismatched base pairs withthe target HIF-1α RNA sequence can be interspersed by nucleotides thatform matched base pairs with the target HIF-1αRNA sequence (e.g., for aDsiRNA possessing mismatch-forming nucleotides at positions 17, 19, 21and 22, but not at positions 18 and 20, the mismatch-forming residues ofantisense strand positions 21 and 22 are adjacent to one another, whilethe mismatch-forming residues of antisense strand positions 17 and 19are interspersed by one nucleotide that forms a matched base pair withthe corresponding residue of the target HIF-1α RNA sequence—similarly,the mismatch-forming residues of antisense strand positions 19 and 21are also interspersed by one nucleotide that forms a matched base pairwith the corresponding residue of the target HIF-1αRNA sequence). Forexample, four residues of the antisense strand (located within themismatch-tolerant region of the antisense strand) that form mismatchedbase pairs with the corresponding target HIF-1α RNA sequence can occurwith zero, one, two or three matched base pairs located between any twoof these mismatch-forming base pairs.

The above DsiRNAmm and other dsRNA structures are described in order toexemplify certain structures of DsiRNAmm and dsRNA agents. Design of theabove DsiRNAmm and dsRNA structures can be adapted to generate, e.g.,DsiRNAmm forms of other DsiRNA structures shown infra. As exemplifiedabove, dsRNAs can also be designed that possess single mismatches (ortwo, three or four mismatches) between the antisense strand of the dsRNAand a target sequence, yet optionally can retain perfect complementaritybetween sense and antisense strand sequences of a dsRNA.

It is further noted that the dsRNA agents exemplified infra can alsopossess insertion/deletion (in/del) structures within theirdouble-stranded and/or target HIF-1α RNA-aligned structures.Accordingly, the dsRNAs of the invention can be designed to possessin/del variations in, e.g., antisense strand sequence as compared totarget HIF-1α RNA sequence and/or antisense strand sequence as comparedto sense strand sequence, with preferred location(s) for placement ofsuch in/del nucleotides corresponding to those locations described abovefor positioning of mismatched and/or mismatch-forming base pairs.

It is also noted that the DsiRNAs of the instant invention can toleratemismatches within the 3′-terminal region of the sense strand/5′-terminalregion of the antisense strand, as this region is modeled to beprocessed by Dicer and liberated from the guide strand sequence thatloads into RISC. Exemplary DsiRNA structures of the invention thatharbor such mismatches include the following:

Target RNA Sequence: 5′-...XXXXXXXXXXXXXXXXXXXXXHXXX...-3′ DsiRNA SenseStrand: 5′-XXXXXXXXXXXXXXXXXXXXXIXDD-3′ DsiRNA Antisense Strand:3′-XXXXXXXXXXXXXXXXXXXXXXXJXXX-5′ Target RNA Sequence:5′-...XXXXXXXXXXXXXXXXXXXXXXHXX...-3′ DsiRNA Sense Strand:5′-XXXXXXXXXXXXXXXXXXXXXXIDD-3′ DsiRNA Antisense Strand:3′-XXXXXXXXXXXXXXXXXXXXXXXXJXX-5′ Target RNA Sequence:5′-...XXXXXXXXXXXXXXXXXXXXXXXHX...-3′ DsiRNA Sense Strand:5′-XXXXXXXXXXXXXXXXXXXXXXXID-3′ DsiRNA Antisense Strand:3′-XXXXXXXXXXXXXXXXXXXXXXXXXJX-5′ Target RNA Sequence:5′-...XXXXXXXXXXXXXXXXXXXXXXXXH...-3′ DsiRNA Sense Strand:5′-XXXXXXXXXXXXXXXXXXXXXXXDI-3′ DsiRNA Antisense Strand:3′-XXXXXXXXXXXXXXXXXXXXXXXXXXJ-5′wherein “X”=RNA, “D”=DNA and “I” and “J”=Nucleic acid residues (RNA, DNAor non-natural or modified nucleic acids) that do not base pair(hydrogen bond) with one another, yet optionally “J” is complementary totarget RNA sequence nucleotide “H”. Any of the residues of such agentscan optionally be 2′-O-methyl RNA monomers—alternating positioning of2′-O-methyl RNA monomers that commences from the 3′-terminal residue ofthe bottom (second) strand, as shown above—or any of the above-describedmethylation patterns—can also be used in the above DsiRNA agents. Theabove mismatches can also be combined within the DsiRNAs of the instantinvention.

In the below structures, such mismatches are introduced within theasymmetric HIF-1α-1385 DsiRNA (newly-introduced mismatch residues areitalicized):

HIF-1α-1385 25/27mer DsiRNA, mismatch position=22 of sense strand (from5′-terminus)

Optionally, the mismatched “A” residue of position 22 of the sensestrand is alternatively “U” or “G”.HIF-1α-1385 25/27mer DsiRNA, mismatch position=23 of sense strand

Optionally, the mismatched “C” residue of position 23 of the sensestrand is alternatively “G” or “U”.HIF-1α-1385 25/27mer DsiRNA, mismatch position=24 of sense strand

Optionally, the mismatched “a” residue of position 24 of the sensestrand is alternatively “g” or “t”.HIF-1α-1385 25/27mer DsiRNA, mismatch position=25 of sense strand

Optionally, the mismatched “a” residue of position 25 of the sensestrand is alternatively “t” or “g”.HIF-1α-1385 25/27mer DsiRNA, mismatch position=1 of antisense strand

Optionally, the mismatched “A” residue of position 1 of the antisensestrand is alternatively “U” or “C”.HIF-1α-1385 25/27mer DsiRNA, mismatch position=2 of antisense strand

Optionally, the mismatched “A” residue of position 2 of the antisensestrand is alternatively “C” or “U”.HIF-1α-1385 25/27mer DsiRNA, mismatch position=3 of antisense strand

Optionally, the mismatched “C” residue of position 3 of the antisensestrand is alternatively “A” or “G”.HIF-1α-1385 25/27mer DsiRNA, mismatch position=4 of antisense strand

Optionally, the mismatched “A” residue of position 4 of the antisensestrand is alternatively “U” or “C”.

As noted above, introduction of such mismatches can be performed uponany of the DsiRNAs described herein.

The mismatches of such DsiRNA structures can be combined to produce aDsiRNA possessing, e.g., two, three or even four mismatches within the3′-terminal four nucleotides of the sense strand/5′-terminal fournucleotides of the antisense strand.

Indeed, in view of the flexibility of sequences which can beincorporated into DsiRNAs at the 3′-terminal residues of the sensestrand/5′-terminal residues of the antisense strand, in certainembodiments, the sequence requirements of an asymmetric DsiRNA of theinstant invention can be represented as the following (minimalist)structure (shown for an exemplary HIF-1α-1385 DsiRNA sequence):

(SEQ ID NO: 2088) 5′-UCAAGCAACUGUCAUAUAUAAXXX[X]_(n)-3′ (SEQ ID NO:2089) 3′-UGAGUUCGUUGACAGUAUAUAXXXXX[X]_(n)-5′where n=1 to 5, 1 to 10, 1 to 20, 1 to 30, 1 to 50, or 1 to 80 or more.

HIF-1α-1385 Target: (SEQ ID NO: 2090) 5′-ACTCAAGCAACTGTCATATATXXXXXX-3′

The HIF-1α target sight may also be a site which is targeted by one ormore of several oligonucleotides whose complementary target sitesoverlap with a stated target site. For example, for an exemplaryHIF-1α-2860 DsiRNA, it is noted that certain DsiRNAs targetingoverlapping and only slightly offset HIF-1α sequences can exhibitactivity levels similar to that of HIF-1α-2860 (specifically, seeHIF-1α-2852, HIF-1α-2856, HIF-1α-2858, HIF-1α-2862 and HIF-1α-2864DsiRNAs of FIG. 3B. Thus, in certain embodiments, a designated targetsequence region can be effectively targeted by a series of DsiRNAspossessing largely overlapping sequences. (E.g., if considering DsiRNAssurrounding the HIF-1α-2860 site, a more encompassing HIF-1α targetsequence might be recited as, e.g.,5′-GGCAGCAGAAACCTACTGCAGGGTGAAGAATTACTCAGA-3′ (SEQ ID NO: 2091), whereinany given DsiRNA (e.g., a DsiRNA selected from HIF-1α-2852, HIF-1α-2853,HIF-1α-2854, HIF-1α-2855, HIF-1α-2856, HIF-1α-2857, HIF-1α-2858,HIF-1α-2859, HIF-1α-2860, HIF-1α-2861, HIF-1α-2862, HIF-1α-2863 andHIF-1α-2864) only targets a sub-sequence within such a sequence region,yet the entire sequence can be considered a viable target for such aseries of DsiRNAs).

Additionally and/or alternatively, mismatches within the 3′-terminalfour nucleotides of the sense strand/5′-terminal four nucleotides of theantisense strand can be combined with mismatches positioned at othermismatch-tolerant positions, as described above.

In view of the present identification of the above-described Dicersubstrate agents (DsiRNAs) as inhibitors of HIF-1α levels via targetingof specific HIF-1α sequences, it is also recognized that dsRNAs havingstructures similar to those described herein can also be synthesizedwhich target other sequences within the HIF-1α sequence of NM_001530.3,NM_181054.2 or NM_010431.2, or within variants thereof (e.g., targetsequences possessing 80% identity, 90% identity, 95% identity, 96%identity, 97% identity, 98% identity, 99% or more identity to a sequenceof NM_001530.3, NM_181054.2 and/or NM_010431.2).

Anti-HIF-1α DsiRNA Design/Synthesis

It has been found empirically that longer dsRNA species of from 25 to 35nucleotides (DsiRNAs) and especially from 25 to 30 nucleotides giveunexpectedly effective results in terms of potency and duration ofaction, as compared to 19-23mer siRNA agents. Without wishing to bebound by the underlying theory of the dsRNA processing mechanism, it isthought that the longer dsRNA species serve as a substrate for the Dicerenzyme in the cytoplasm of a cell. In addition to cleaving the dsRNA ofthe invention into shorter segments, Dicer is thought to facilitate theincorporation of a single-stranded cleavage product derived from thecleaved dsRNA into the RISC complex that is responsible for thedestruction of the cytoplasmic RNA (e.g., HIF-1α RNA) of or derived fromthe target gene, HIF-1α (or other gene associated with aHIF-1α-associated disease or disorder). Prior studies (Rossi et al.,U.S. Patent Application No. 2007/0265220) have shown that thecleavability of a dsRNA species (specifically, a DsiRNA agent) by Dicercorresponds with increased potency and duration of action of the dsRNAspecies.

Certain preferred anti-HIF-1α DsiRNA agents were selected from apre-screened population. Design of DsiRNAs can optionally involve use ofpredictive scoring algorithms that perform in silico assessments of theprojected activity/efficacy of a number of possible DsiRNA agentsspanning a region of sequence. Information regarding the design of suchscoring algorithms can be found, e.g., in Gong et al. (BMCBioinformatics 2006, 7:516), though a more recent “v3” algorithmrepresents a theoretically improved algorithm relative to siRNA scoringalgorithms previously available in the art. (E.g., the “v3” and “v4”scoring algorithms are machine learning algorithms that are not reliantupon any biases in human sequence. In addition, the “v3” and “v4”algorithms derive from data sets that are many-fold larger than thatfrom which an older “v2” algorithm such as that described in Gong et al.derives.)

The first and second oligonucleotides of the DsiRNA agents of theinstant invention are not required to be completely complementary. Infact, in one embodiment, the 3′-terminus of the sense strand containsone or more mismatches. In one aspect, two mismatches are incorporatedat the 3′ terminus of the sense strand. In another embodiment, theDsiRNA of the invention is a double stranded RNA molecule containing twoRNA oligonucleotides each of which is 27 nucleotides in length and, whenannealed to each other, have blunt ends and a two nucleotide mismatch onthe 3′-terminus of the sense strand (the 5′-terminus of the antisensestrand). The use of mismatches or decreased thermodynamic stability(specifically at the 3′-sense/5′-antisense position) has been proposedto facilitate or favor entry of the antisense strand into RISC (Schwarzet al., 2003, Cell 115: 199-208; Khvorova et al., 2003, Cell 115:209-216), presumably by affecting some rate-limiting unwinding stepsthat occur with entry of the siRNA into RISC. Thus, terminal basecomposition has been included in design algorithms for selecting active21mer siRNA duplexes (Ui-Tei et al., 2004, Nucleic Acids Res 32:936-948; Reynolds et al., 2004, Nat Biotechnol 22: 326-330). With Dicercleavage of the dsRNA of this embodiment, the small end-terminalsequence which contains the mismatches will either be left unpaired withthe antisense strand (become part of a 3′-overhang) or be cleavedentirely off the final 21-mer siRNA. These “mismatches”, therefore, donot persist as mismatches in the final RNA component of RISC. Thefinding that base mismatches or destabilization of segments at the3′-end of the sense strand of Dicer substrate improved the potency ofsynthetic duplexes in RNAi, presumably by facilitating processing byDicer, was a surprising finding of past works describing the design anduse of 25-30mer dsRNAs (also termed “DsiRNAs” herein; Rossi et al., U.S.Patent Application Nos. 2005/0277610, 2005/0244858 and 2007/0265220).

Modification of Anti-HIF-1α dsRNAs

One major factor that inhibits the effect of double stranded RNAs(“dsRNAs”) is the degradation of dsRNAs (e.g., siRNAs and DsiRNAs) bynucleases. A 3′-exonuclease is the primary nuclease activity present inserum and modification of the 3′-ends of antisense DNA oligonucleotidesis crucial to prevent degradation (Eder et al., 1991, Antisense Res Dev,1: 141-151). An RNase-T family nuclease has been identified called ERI-1which has 3′ to 5′ exonuclease activity that is involved in regulationand degradation of siRNAs (Kennedy et al., 2004, Nature 427: 645-649;Hong et al., 2005, Biochem J, 390: 675-679). This gene is also known asThex1 (NM_02067) in mice or THEX1 (NM_153332) in humans and is involvedin degradation of histone mRNA; it also mediates degradation of3′-overhangs in siRNAs, but does not degrade duplex RNA (Yang et al.,2006, J Biol Chem, 281: 30447-30454). It is therefore reasonable toexpect that 3′-end-stabilization of dsRNAs, including the DsiRNAs of theinstant invention, will improve stability.

XRN1 (NM_019001) is a 5′ to 3′ exonuclease that resides in P-bodies andhas been implicated in degradation of mRNA targeted by miRNA (Rehwinkelet al., 2005, RNA 11: 1640-1647) and may also be responsible forcompleting degradation initiated by internal cleavage as directed by asiRNA. XRN2 (NM_012255) is a distinct 5′ to 3′ exonuclease that isinvolved in nuclear RNA processing.

RNase A is a major endonuclease activity in mammals that degrades RNAs.It is specific for ssRNA and cleaves at the 3′-end of pyrimidine bases.SiRNA degradation products consistent with RNase A cleavage can bedetected by mass spectrometry after incubation in serum (Turner et al.,2007, Mol Biosyst 3: 43-50). The 3′-overhangs enhance the susceptibilityof siRNAs to RNase degradation. Depletion of RNase A from serum reducesdegradation of siRNAs; this degradation does show some sequencepreference and is worse for sequences having poly A/U sequence on theends (Haupenthal et al., 2006 Biochem Pharmacol 71: 702-710). Thissuggests the possibility that lower stability regions of the duplex may“breathe” and offer transient single-stranded species available fordegradation by RNase A. RNase A inhibitors can be added to serum andimprove siRNA longevity and potency (Haupenthal et al., 2007, Int J.Cancer 121: 206-210).

In 21mers, phosphorothioate or boranophosphate modifications directlystabilize the internucleoside phosphate linkage. Boranophosphatemodified RNAs are highly nuclease resistant, potent as silencing agents,and are relatively non-toxic. Boranophosphate modified RNAs cannot bemanufactured using standard chemical synthesis methods and instead aremade by in vitro transcription (IVT) (Hall et al., 2004, Nucleic AcidsRes 32: 5991-6000; Hall et al., 2006, Nucleic Acids Res 34: 2773-2781).Phosphorothioate (PS) modifications can be easily placed in the RNAduplex at any desired position and can be made using standard chemicalsynthesis methods. The PS modification shows dose-dependent toxicity, somost investigators have recommended limited incorporation in siRNAs,favoring the 3′-ends where protection from nucleases is most important(Harborth et al., 2003, Antisense Nucleic Acid Drug Dev 13: 83-105; Chiuand Rana, 2003, Mol Cell 10: 549-561; Braasch et al., 2003, Biochemistry42: 7967-7975; Amarzguioui et al., 2003, Nucleic Acids Research 31:589-595). More extensive PS modification can be compatible with potentRNAi activity; however, use of sugar modifications (such as 2′-O-methylRNA) may be superior (Choung et al., 2006, Biochem Biophys Res Commun342: 919-927).

A variety of substitutions can be placed at the 2′-position of theribose which generally increases duplex stability (T_(m)) and cangreatly improve nuclease resistance. 2′-O-methyl RNA is a naturallyoccurring modification found in mammalian ribosomal RNAs and transferRNAs. 2′-O-methyl modification in siRNAs is known, but the preciseposition of modified bases within the duplex is important to retainpotency and complete substitution of 2′-O-methyl RNA for RNA willinactivate the siRNA. For example, a pattern that employs alternating2′-O-methyl bases can have potency equivalent to unmodified RNA and isquite stable in serum (Choung et al., 2006, Biochem Biophys Res Commun342: 919-927; Czauderna et al., 2003, Nucleic Acids Research 31:2705-2716).

The 2′-fluoro (2′-F) modification is also compatible with dsRNA (e.g.,siRNA and DsiRNA) function; it is most commonly placed at pyrimidinesites (due to reagent cost and availability) and can be combined with2′-O-methyl modification at purine positions; 2′-F purines are availableand can also be used. Heavily modified duplexes of this kind can bepotent triggers of RNAi in vitro (Allerson et al., 2005, J Med Chem 48:901-904; Prakash et al., 2005, J Med Chem 48: 4247-4253; Kraynack andBaker, 2006, RNA 12: 163-176) and can improve performance and extendduration of action when used in vivo (Morrissey et al., 2005, Hepatology41: 1349-1356; Morrissey et al., 2005, Nat Biotechnol 23: 1002-1007). Ahighly potent, nuclease stable, blunt 19mer duplex containingalternative 2′-F and 2′-O-Me bases is taught by Allerson. In thisdesign, alternating 2′-O-Me residues are positioned in an identicalpattern to that employed by Czauderna, however the remaining RNAresidues are converted to 2′-F modified bases. A highly potent, nucleaseresistant siRNA employed by Morrissey employed a highly potent, nucleaseresistant siRNA in vivo. In addition to 2′-O-Me RNA and 2′-F RNA, thisduplex includes DNA, RNA, inverted abasic residues, and a 3′-terminal PSinternucleoside linkage. While extensive modification has certainbenefits, more limited modification of the duplex can also improve invivo performance and is both simpler and less costly to manufacture.Soutschek et al. (2004, Nature 432: 173-178) employed a duplex in vivoand was mostly RNA with two 2′-O-Me RNA bases and limited 3′-terminal PSinternucleoside linkages.

Locked nucleic acids (LNAs) are a different class of 2′-modificationthat can be used to stabilize dsRNA (e.g., siRNA and DsiRNA). Patternsof LNA incorporation that retain potency are more restricted than2′-O-methyl or 2′-F bases, so limited modification is preferred (Braaschet al., 2003, Biochemistry 42: 7967-7975; Grunweller et al., 2003,Nucleic Acids Res 31: 3185-3193; Elmen et al., 2005, Nucleic Acids Res33: 439-447). Even with limited incorporation, the use of LNAmodifications can improve dsRNA performance in vivo and may also alteror improve off target effect profiles (Mook et al., 2007, Mol CancerTher 6: 833-843).

Synthetic nucleic acids introduced into cells or live animals can berecognized as “foreign” and trigger an immune response. Immunestimulation constitutes a major class of off-target effects which candramatically change experimental results and even lead to cell death.The innate immune system includes a collection of receptor moleculesthat specifically interact with DNA and RNA that mediate theseresponses, some of which are located in the cytoplasm and some of whichreside in endosomes (Marques and Williams, 2005, Nat Biotechnol 23:1399-1405; Schlee et al., 2006, Mol Ther 14: 463-470). Delivery ofsiRNAs by cationic lipids or liposomes exposes the siRNA to bothcytoplasmic and endosomal compartments, maximizing the risk fortriggering a type 1 interferon (IFN) response both in vitro and in vivo(Morrissey et al., 2005, Nat Biotechnol 23: 1002-1007; Sioud andSorensen, 2003, Biochem Biophys Res Commun 312: 1220-1225; Sioud, 2005,J Mol Riot 348: 1079-1090; Ma et al., 2005, Biochem Biophys Res Commun330: 755-759). RNAs transcribed within the cell are less immunogenic(Robbins et al., 2006, Nat Biotechnol 24: 566-571) and synthetic RNAsthat are immunogenic when delivered using lipid-based methods can evadeimmune stimulation when introduced unto cells by mechanical means, evenin vivo (Heidel et al., 2004, Nat Biotechnol 22: 1579-1582). However,lipid based delivery methods are convenient, effective, and widely used.Some general strategy to prevent immune responses is needed, especiallyfor in vivo application where all cell types are present and the risk ofgenerating an immune response is highest. Use of chemically modifiedRNAs may solve most or even all of these problems.

In certain embodiments, modifications can be included in the anti-HIF-1αdsRNA agents of the present invention so long as the modification doesnot prevent the dsRNA agent from possessing HIF-1α inhibitory activity.In one embodiment, one or more modifications are made that enhance Dicerprocessing of the DsiRNA agent (an assay for determining Dicerprocessing of a DsiRNA is described elsewhere herein). In a secondembodiment, one or more modifications are made that result in moreeffective HIF-1α inhibition (as described herein, HIF-1αinhibition/HIF-1α inhibitory activity of a dsRNA can be assayed viaart-recognized methods for determining RNA levels, or for determiningHIF-1α polypeptide levels, should such levels be assessed in lieu of orin addition to assessment of, e.g., HIF-1α mRNA levels). In a thirdembodiment, one or more modifications are made that support greaterHIF-1α inhibitory activity (means of determining HIF-1α inhibitoryactivity are described supra). In a fourth embodiment, one or moremodifications are made that result in greater potency of HIF-1αinhibitory activity per each dsRNA agent molecule to be delivered to thecell (potency of HIF-1α inhibitory activity is described supra).Modifications can be incorporated in the 3′-terminal region, the5′-terminal region, in both the 3′-terminal and 5′-terminal region or insome instances in various positions within the sequence. With therestrictions noted above in mind, numbers and combinations ofmodifications can be incorporated into the dsRNA agent. Where multiplemodifications are present, they may be the same or different.Modifications to bases, sugar moieties, the phosphate backbone, andtheir combinations are contemplated. Either 5′-terminus can bephosphorylated.

Examples of modifications contemplated for the phosphate backboneinclude phosphonates, including methylphosphonate, phosphorothioate, andphosphotriester modifications such as alkylphosphotriesters, and thelike. Examples of modifications contemplated for the sugar moietyinclude 2′-alkyl pyrimidine, such as 2′-O-methyl, 2′-fluoro, amino, anddeoxy modifications and the like (see, e.g., Amarzguioui et al., 2003,Nucleic Acids Research 31: 589-595). Examples of modificationscontemplated for the base groups include abasic sugars, 2-O-alkylmodified pyrimidines, 4-thiouracil, 5-bromouracil, 5-iodouracil, and5-(3-aminoallyl)-uracil and the like. Locked nucleic acids, or LNA's,could also be incorporated. Many other modifications are known and canbe used so long as the above criteria are satisfied. Examples ofmodifications are also disclosed in U.S. Pat. Nos. 5,684,143, 5,858,988and 6,291,438 and in U.S. published patent application No. 2004/0203145A1. Other modifications are disclosed in Herdewijn (2000, AntisenseNucleic Acid Drug Dev 10: 297-310), Eckstein (2000, Antisense NucleicAcid Drug Dev 10: 117-21), Rusckowski et al. (2000, Antisense NucleicAcid Drug Dev 10: 333-345), Stein et al. (2001, Antisense Nucleic AcidDrug Dev 11: 317-25); Vorobjev et al. (2001, Antisense Nucleic Acid DrugDev 11: 77-85).

One or more modifications contemplated can be incorporated into eitherstrand. The placement of the modifications in the dsRNA agent cangreatly affect the characteristics of the dsRNA agent, includingconferring greater potency and stability, reducing toxicity, enhanceDicer processing, and minimizing an immune response. In one embodiment,the antisense strand or the sense strand or both strands have one ormore 2′-O-methyl modified nucleotides. In another embodiment, theantisense strand contains 2′-O-methyl modified nucleotides. In anotherembodiment, the antisense stand contains a 3′ overhang that is comprisedof 2′-O-methyl modified nucleotides. The antisense strand could alsoinclude additional 2′-O-methyl modified nucleotides.

In certain embodiments, the anti-HIF-1α DsiRNA agent of the inventionhas several properties which enhance its processing by Dicer. Accordingto such embodiments, the DsiRNA agent has a length sufficient such thatit is processed by Dicer to produce an siRNA and at least one of thefollowing properties: (i) the DsiRNA agent is asymmetric, e.g., has a 3′overhang on the sense strand and (ii) the DsiRNA agent has a modified 3′end on the antisense strand to direct orientation of Dicer binding andprocessing of the dsRNA to an active siRNA. According to theseembodiments, the longest strand in the DsiRNA agent comprises 25-30nucleotides. In one embodiment, the sense strand comprises 25-30nucleotides and the antisense strand comprises 25-28 nucleotides. Thus,the resulting dsRNA has an overhang on the 3′ end of the sense strand.The overhang is 1-4 nucleotides, such as 2 nucleotides. The antisensestrand may also have a 5′ phosphate.

In certain embodiments, the sense strand of a DsiRNA agent is modifiedfor Dicer processing by suitable modifiers located at the 3′ end of thesense strand, i.e., the DsiRNA agent is designed to direct orientationof Dicer binding and processing. Suitable modifiers include nucleotidessuch as deoxyribonucleotides, dideoxyribonucleotides, acyclonucleotidesand the like and sterically hindered molecules, such as fluorescentmolecules and the like. Acyclonucleotides substitute a2-hydroxyethoxymethyl group for the 2′-deoxyribofuranosyl sugar normallypresent in dNMPs. Other nucleotide modifiers could include3′-deoxyadenosine (cordycepin), 3′-azido-3′-deoxythymidine (AZT),2′,3′-dideoxyinosine (ddI), 2′,3′-dideoxy-3′-thiacytidine (3TC),2′,3′-didehydro-2′,3′-dideoxythymidine (d4T) and the monophosphatenucleotides of 3′-azido-3′-deoxythymidine (AZT),2′,3′-dideoxy-3′-thiacytidine (3TC) and2′,3′-didehydro-2′,3′-dideoxythymidine (d4T). In one embodiment,deoxynucleotides are used as the modifiers. When nucleotide modifiersare utilized, 1-3 nucleotide modifiers, or 2 nucleotide modifiers aresubstituted for the ribonucleotides on the 3′ end of the sense strand.When sterically hindered molecules are utilized, they are attached tothe ribonucleotide at the 3′ end of the antisense strand. Thus, thelength of the strand does not change with the incorporation of themodifiers. In another embodiment, the invention contemplatessubstituting two DNA bases in the dsRNA to direct the orientation ofDicer processing. In a further invention, two terminal DNA bases arelocated on the 3′ end of the sense strand in place of tworibonucleotides forming a blunt end of the duplex on the 5′ end of theantisense strand and the 3′ end of the sense strand, and atwo-nucleotide RNA overhang is located on the 3′-end of the antisensestrand. This is an asymmetric composition with DNA on the blunt end andRNA bases on the overhanging end.

In certain other embodiments, the antisense strand of a DsiRNA agent ismodified for Dicer processing by suitable modifiers located at the 3′end of the antisense strand, i.e., the DsiRNA agent is designed todirect orientation of Dicer binding and processing. Suitable modifiersinclude nucleotides such as deoxyribonucleotides,dideoxyribonucleotides, acyclonucleotides and the like and stericallyhindered molecules, such as fluorescent molecules and the like.Acyclonucleotides substitute a 2-hydroxyethoxymethyl group for the2′-deoxyribofuranosyl sugar normally present in dNMPs. Other nucleotidemodifiers could include 3′-deoxyadenosine (cordycepin),3′-azido-3′-deoxythymidine (AZT), 2′,3′-dideoxyinosine (ddI),2′,3′-dideoxy-3′-thiacytidine (3TC),2′,3′-didehydro-2′,3′-dideoxythymidine (d4T) and the monophosphatenucleotides of 3′-azido-3′-deoxythymidine (AZT),2′,3′-dideoxy-3′-thiacytidine (3TC) and2′,3′-didehydro-2′,3′-dideoxythymidine (d4T). In one embodiment,deoxynucleotides are used as the modifiers. When nucleotide modifiersare utilized, 1-3 nucleotide modifiers, or 2 nucleotide modifiers aresubstituted for the ribonucleotides on the 3′ end of the antisensestrand. When sterically hindered molecules are utilized, they areattached to the ribonucleotide at the 3′ end of the antisense strand.Thus, the length of the strand does not change with the incorporation ofthe modifiers. In another embodiment, the invention contemplatessubstituting two DNA bases in the dsRNA to direct the orientation ofDicer processing. In a further invention, two terminal DNA bases arelocated on the 3′ end of the antisense strand in place of tworibonucleotides forming a blunt end of the duplex on the 5′ end of thesense strand and the 3′ end of the antisense strand, and atwo-nucleotide RNA overhang is located on the 3′-end of the sensestrand. This is also an asymmetric composition with DNA on the blunt endand RNA bases on the overhanging end.

The sense and antisense strands anneal under biological conditions, suchas the conditions found in the cytoplasm of a cell. In addition, aregion of one of the sequences, particularly of the antisense strand, ofthe dsRNA has a sequence length of at least 19 nucleotides, whereinthese nucleotides are adjacent to the 3′ end of antisense strand and aresufficiently complementary to a nucleotide sequence of the target HIF-1αRNA.

Additionally, the DsiRNA agent structure can be optimized to ensure thatthe oligonucleotide segment generated from Dicer's cleavage will be theportion of the oligonucleotide that is most effective in inhibiting geneexpression. For example, in one embodiment of the invention, a 27-bpoligonucleotide of the DsiRNA agent structure is synthesized wherein theanticipated 21 to 22-bp segment that will inhibit gene expression islocated on the 3′-end of the antisense strand. The remaining baseslocated on the 5′-end of the antisense strand will be cleaved by Dicerand will be discarded. This cleaved portion can be homologous (i.e.,based on the sequence of the target sequence) or non-homologous andadded to extend the nucleic acid strand.

US 2007/0265220 discloses that 27mer DsiRNAs show improved stability inserum over comparable 21mer siRNA compositions, even absent chemicalmodification. Modifications of DsiRNA agents, such as inclusion of2′-O-methyl RNA in the antisense strand, in patterns such as detailedabove, when coupled with addition of a 5′ Phosphate, can improvestability of DsiRNA agents. Addition of 5′-phosphate to all strands insynthetic RNA duplexes may be an inexpensive and physiological method toconfer some limited degree of nuclease stability.

The chemical modification patterns of the dsRNA agents of the instantinvention are designed to enhance the efficacy of such agents.Accordingly, such modifications are designed to avoid reducing potencyof dsRNA agents; to avoid interfering with Dicer processing of DsiRNAagents; to improve stability in biological fluids (reduce nucleasesensitivity) of dsRNA agents; or to block or evade detection by theinnate immune system. Such modifications are also designed to avoidbeing toxic and to avoid increasing the cost or impact the ease ofmanufacturing the instant dsRNA agents of the invention.

In certain embodiments of the present invention, an anti-HIF-1α DsiRNAagent has one or more of the following properties: (i) the DsiRNA agentis asymmetric, e.g., has a 3′ overhang on the antisense strand and (ii)the DsiRNA agent has a modified 3′ end on the sense strand to directorientation of Dicer binding and processing of the dsRNA to an activesiRNA. According to this embodiment, the longest strand in the dsRNAcomprises 25-35 nucleotides (e.g., 25, 26, 27, 28, 29, 30, 31, 32, 33,34 or 35 nucleotides). In certain such embodiments, the DsiRNA agent isasymmetric such that the sense strand comprises 25-34 nucleotides andthe 3′ end of the sense strand forms a blunt end with the 5′ end of theantisense strand while the antisense strand comprises 26-35 nucleotidesand forms an overhang on the 3′ end of the antisense strand. In oneembodiment, the DsiRNA agent is asymmetric such that the sense strandcomprises 25-28 nucleotides and the antisense strand comprises 25-30nucleotides. Thus, the resulting dsRNA has an overhang on the 3′ end ofthe antisense strand. The overhang is 1-4 nucleotides, for example 2nucleotides. The sense strand may also have a 5′ phosphate.

The DsiRNA agent can also have one or more of the following additionalproperties: (a) the antisense strand has a right shift from the typical21mer (e.g., the DsiRNA comprises a length of antisense strandnucleotides that extends to the 5′ of a projected Dicer cleavage sitewithin the DsiRNA, with such antisense strand nucleotides base pairedwith corresponding nucleotides of the sense strand extending 3′ of aprojected Dicer cleavage site in the sense strand), (b) the strands maynot be completely complementary, i.e., the strands may contain simplemismatched base pairs (in certain embodiments, the DsiRNAs of theinvention possess 1, 2, 3, 4 or even 5 or more mismatched base pairs,provided that HIF-1α inhibitory activity of the DsiRNA possessingmismatched base pairs is retained at sufficient levels (e.g., retains atleast 50% HIF-1α inhibitory activity or more, at least 60% HIF-1αinhibitory activity or more, at least 70% HIF-1α inhibitory activity ormore, at least 80% HIF-1α inhibitory activity or more, at least 90%HIF-1α inhibitory activity or more or at least 95% HIF-1α inhibitoryactivity or more as compared to a corresponding DsiRNA not possessingmismatched base pairs. In certain embodiments, mismatched base pairsexist between the antisense and sense strands of a DsiRNA. In someembodiments, mismatched base pairs exist (or are predicted to exist)between the antisense strand and the target RNA. In certain embodiments,the presence of a mismatched base pair(s) between an antisense strandresidue and a corresponding residue within the target RNA that islocated 3′ in the target RNA sequence of a projected Ago2 cleavage siteretains and may even enhance HIF-1α inhibitory activity of a DsiRNA ofthe invention) and (c) base modifications such as locked nucleic acid(s)may be included in the 5′ end of the sense strand. A “typical” 21mersiRNA is designed using conventional techniques. In one technique, avariety of sites are commonly tested in parallel or pools containingseveral distinct siRNA duplexes specific to the same target with thehope that one of the reagents will be effective (Ji et al., 2003, FEBSLett 552: 247-252). Other techniques use design rules and algorithms toincrease the likelihood of obtaining active RNAi effector molecules(Schwarz et al., 2003, Cell 115: 199-208; Khvorova et al., 2003, Cell115: 209-216; Ui-Tei et al., 2004, Nucleic Acids Res 32: 936-948;Reynolds et al., 2004, Nat Biotechnol 22: 326-330; Krol et al., 2004, JBiol Chem 279: 42230-42239; Yuan et al., 2004, Nucl Acids Res32(Webserver issue):W130-134; Boese et al., 2005, Methods Enzymol 392:73-96). High throughput selection of siRNA has also been developed (U.S.published patent application No. 2005/0042641 A1). Potential targetsites can also be analyzed by secondary structure predictions (Heale etal., 2005, Nucleic Acids Res 33(3): e30). This 21mer is then used todesign a right shift to include 3-9 additional nucleotides on the 5′ endof the 21mer. The sequence of these additional nucleotides is notrestricted. In one embodiment, the added ribonucleotides are based onthe sequence of the target gene. Even in this embodiment, fullcomplementarity between the target sequence and the antisense siRNA isnot required.

The first and second oligonucleotides of a DsiRNA agent of the instantinvention are not required to be completely complementary. They onlyneed to be sufficiently complementary to anneal under biologicalconditions and to provide a substrate for Dicer that produces a siRNAsufficiently complementary to the target sequence. Locked nucleic acids,or LNA's, are well known to a skilled artisan (Elmen et al., 2005,Nucleic Acids Res 33: 439-447; Kurreck et al., 2002, Nucleic Acids Res30: 1911-1918; Crinelli et al., 2002, Nucleic Acids Res 30: 2435-2443;Braasch and Corey, 2001, Chem Biol 8: 1-7; Bondensgaard et al., 2000,Chemistry 6: 2687-2695; Wahlestedt et al., 2000, Proc Natl Acad Sci USA97: 5633-5638). In one embodiment, an LNA is incorporated at the 5′terminus of the sense strand. In another embodiment, an LNA isincorporated at the 5′ terminus of the sense strand in duplexes designedto include a 3′ overhang on the antisense strand.

In certain embodiments, the DsiRNA agent of the instant invention has anasymmetric structure, with the sense strand having a 25-base pairlength, and the antisense strand having a 27-base pair length with a 2base 3′-overhang. In other embodiments, this DsiRNA agent having anasymmetric structure further contains 2 deoxynucleotides at the 3′ endof the sense strand in place of two of the ribonucleotides.

Certain DsiRNA agent compositions containing two separateoligonucleotides can be linked by a third structure. The third structurewill not block Dicer activity on the DsiRNA agent and will not interferewith the directed destruction of the RNA transcribed from the targetgene. In one embodiment, the third structure may be a chemical linkinggroup. Many suitable chemical linking groups are known in the art andcan be used. Alternatively, the third structure may be anoligonucleotide that links the two oligonucleotides of the DsiRNA agentin a manner such that a hairpin structure is produced upon annealing ofthe two oligonucleotides making up the dsRNA composition. The hairpinstructure will not block Dicer activity on the DsiRNA agent and will notinterfere with the directed destruction of the HIF-1α RNA.

HIF-1α cDNA and Polypeptide Sequences

Known human and mouse HIF-1α cDNA and polypeptide sequences include thefollowing: human wild-type Hypoxia Inducible Factor 1, alpha subunit(basic helix-loop-helix transcription factor; HIF-1α) cDNA sequencesGenBank Accession Nos. NM_001530.3 (transcript variant 1) andNM_181054.2 (transcript variant 2); corresponding human HIF-1αpolypeptide sequences GenBank Accession Nos. NP_001521.1 (transcriptvariant 1) and NP_851397.1 (transcript variant 2); mouse wild-typeHIF-1α sequence GenBank Accession No. NM_010431.2 (Mus musculus C57BL/6HIF-1α transcript) and corresponding mouse HIF-1α polypeptide sequenceGenBank Accession No. NP_034561.2.

In Vitro Assay to Assess dsRNA HIF-1α Inhibitory Activity

An in vitro assay that recapitulates RNAi in a cell-free system can beused to evaluate dsRNA constructs targeting HIF-1α RNA sequence(s), andthus to assess HIF-1α-specific gene inhibitory activity (also referredto herein as HIF-1α inhibitory activity) of a dsRNA. The assay comprisesthe system described by Tuschl et al., 1999, Genes and Development, 13,3191-3197 and Zamore et al., 2000, Cell, 101, 25-33 adapted for use withdsRNA (e.g., DsiRNA) agents directed against HIF-1α RNA. A Drosophilaextract derived from syncytial blastoderm is used to reconstitute RNAiactivity in vitro. Target RNA is generated via in vitro transcriptionfrom a selected HIF-1α expressing plasmid using T7 RNA polymerase or viachemical synthesis. Sense and antisense dsRNA strands (for example, 20uM each) are annealed by incubation in buffer (such as 100 mM potassiumacetate, 30 mM HEPES-KOH, pH 7.4, 2 mM magnesium acetate) for 1 minuteat 90° C. followed by 1 hour at 37° C., then diluted in lysis buffer(for example 100 mM potassium acetate, 30 mM HEPES-KOH at pH 7.4, 2 mMmagnesium acetate) Annealing can be monitored by gel electrophoresis onan agarose gel in TBE buffer and stained with ethidium bromide. TheDrosophila lysate is prepared using zero to two-hour-old embryos fromOregon R flies collected on yeasted molasses agar that are dechorionatedand lysed. The lysate is centrifuged and the supernatant isolated. Theassay comprises a reaction mixture containing 50% lysate [vol/vol], RNA(10-50 pM final concentration), and 10% [vol/vol] lysis buffercontaining dsRNA (10 nM final concentration). The reaction mixture alsocontains 10 mM creatine phosphate, 10 ug/ml creatine phosphokinase, 100um GTP, 100 uM UTP, 100 uM CTP, 500 uM ATP, 5 mM DTT, 0.1 U/uL RNasin(Promega), and 100 uM of each amino acid. The final concentration ofpotassium acetate is adjusted to 100 mM. The reactions are pre-assembledon ice and preincubated at 25° C. for 10 minutes before adding RNA, thenincubated at 25° C. for an additional 60 minutes. Reactions are quenchedwith 4 volumes of 1.25× Passive Lysis Buffer (Promega). Target RNAcleavage is assayed by RT-PCR analysis or other methods known in the artand are compared to control reactions in which dsRNA is omitted from thereaction.

Alternately, internally-labeled target RNA for the assay is prepared byin vitro transcription in the presence of [α-³²P] CTP, passed over a G50Sephadex column by spin chromatography and used as target RNA withoutfurther purification. Optionally, target RNA is 5′-³²P-end labeled usingT4 polynucleotide kinase enzyme. Assays are performed as described aboveand target RNA and the specific RNA cleavage products generated by RNAiare visualized on an autoradiograph of a gel. The percentage of cleavageis determined by PHOSPHOR IMAGER® (autoradiography) quantitation ofbands representing intact control RNA or RNA from control reactionswithout dsRNA and the cleavage products generated by the assay.

In one embodiment, this assay is used to determine target sites in theHIF-1α RNA target for dsRNA mediated RNAi cleavage, wherein a pluralityof dsRNA constructs are screened for RNAi mediated cleavage of theHIF-1α RNA target, for example, by analyzing the assay reaction byelectrophoresis of labeled target RNA, or by northern blotting, as wellas by other methodology well known in the art.

In certain embodiments, a dsRNA of the invention is deemed to possessHIF-1α inhibitory activity if, e.g., a 50% reduction in HIF-1α RNAlevels is observed in a system, cell, tissue or organism, relative to asuitable control. Additional metes and bounds for determination ofHIF-1α inhibitory activity of a dsRNA of the invention are describedsupra.

Conjugation and Delivery of Anti-HIF-1α dsRNA Agents

In certain embodiments the present invention relates to a method fortreating a subject having a HIF-1α-associated disease or disorder, or atrisk of developing a HIF-1α-associated disease or disorder. In suchembodiments, the dsRNA can act as novel therapeutic agents forcontrolling the HIF-1α-associated disease or disorder. The methodcomprises administering a pharmaceutical composition of the invention tothe patient (e.g., human), such that the expression, level and/oractivity of a HIF-1α RNA is reduced. The expression, level and/oractivity of a polypeptide encoded by a HIF-1α RNA might also be reducedby a dsRNA of the instant invention, even where said dsRNA is directedagainst a non-coding region of the HIF-1α transcript (e.g., a targeted5′ UTR or 3′ UTR sequence). Because of their high specificity, thedsRNAs of the present invention can specifically target HIF-1α sequencesof cells and tissues, optionally in an allele-specific manner wherepolymorphic alleles exist within an individual and/or population.

In the treatment of a HIF-1α-associated disease or disorder, the dsRNAcan be brought into contact with the cells or tissue of a subject, e.g.,the cells or tissue of a subject exhibiting disregulation of HIF-1αand/or otherwise targeted for reduction of HIF-1α levels. For example,dsRNA substantially identical to all or part of a HIF-1α RNA sequence,may be brought into contact with or introduced into such a cell, eitherin vivo or in vitro. Similarly, dsRNA substantially identical to all orpart of a HIF-1α RNA sequence may administered directly to a subjecthaving or at risk of developing a HIF-1α-associated disease or disorder.

Therapeutic use of the dsRNA agents of the instant invention can involveuse of formulations of dsRNA agents comprising multiple different dsRNAagent sequences. For example, two or more, three or more, four or more,five or more, etc. of the presently described agents can be combined toproduce a formulation that, e.g., targets multiple different regions ofthe HIF-1α RNA, or that not only target HIF-1α RNA but also target,e.g., cellular target genes associated with a HIF-1α-associated diseaseor disorder. A dsRNA agent of the instant invention may also beconstructed such that either strand of the dsRNA agent independentlytargets two or more regions of HIF-1α RNA, or such that one of thestrands of the dsRNA agent targets a cellular target gene of HIF-1αknown in the art.

Use of multifunctional dsRNA molecules that target more then one regionof a target nucleic acid molecule can also provide potent inhibition ofHIF-1α RNA levels and expression. For example, a single multifunctionaldsRNA construct of the invention can target both the HIF-1α-1385 andHIF-1α-4012 sites simultaneously; additionally and/or alternatively,single or multifunctional agents of the invention can be designed toselectively target one splice variant of HIF-1α over another.

Thus, the dsRNA agents of the instant invention, individually, or incombination or in conjunction with other drugs, can be used to treat,inhibit, reduce, or prevent a HIF-1α-associated disease or disorder. Forexample, the dsRNA molecules can be administered to a subject or can beadministered to other appropriate cells evident to those skilled in theart, individually or in combination with one or more drugs underconditions suitable for the treatment.

The dsRNA molecules also can be used in combination with other knowntreatments to treat, inhibit, reduce, or prevent a HIF-1α-associateddisease or disorder in a subject or organism. For example, the describedmolecules could be used in combination with one or more known compounds,treatments, or procedures to treat, inhibit, reduce, or prevent aHIF-1α-associated disease or disorder in a subject or organism as areknown in the art.

A dsRNA agent of the invention can be conjugated (e.g., at its 5′ or 3′terminus of its sense or antisense strand) or unconjugated to anothermoiety (e.g. a non-nucleic acid moiety such as a peptide), an organiccompound (e.g., a dye, cholesterol, or the like). Modifying dsRNA agentsin this way may improve cellular uptake or enhance cellular targetingactivities of the resulting dsRNA agent derivative as compared to thecorresponding unconjugated dsRNA agent, are useful for tracing the dsRNAagent derivative in the cell, or improve the stability of the dsRNAagent derivative compared to the corresponding unconjugated dsRNA agent.

Methods of Introducing Nucleic Acids, Vectors, and Host Cells

dsRNA agents of the invention may be directly introduced into a cell(i.e., intracellularly); or introduced extracellularly into a cavity,interstitial space, into the circulation of an organism, introducedorally, or may be introduced by bathing a cell or organism in a solutioncontaining the nucleic acid. Vascular or extravascular circulation, theblood or lymph system, and the cerebrospinal fluid are sites where thenucleic acid may be introduced.

The dsRNA agents of the invention can be introduced using nucleic aciddelivery methods known in art including injection of a solutioncontaining the nucleic acid, bombardment by particles covered by thenucleic acid, soaking the cell or organism in a solution of the nucleicacid, or electroporation of cell membranes in the presence of thenucleic acid. Other methods known in the art for introducing nucleicacids to cells may be used, such as lipid-mediated carrier transport,chemical-mediated transport, and cationic liposome transfection such ascalcium phosphate, and the like. The nucleic acid may be introducedalong with other components that perform one or more of the followingactivities: enhance nucleic acid uptake by the cell or otherwiseincrease inhibition of the target HIF-1α RNA.

A cell having a target HIF-1α RNA may be from the germ line or somatic,totipotent or pluripotent, dividing or non-dividing, parenchyma orepithelium, immortalized or transformed, or the like. The cell may be astem cell or a differentiated cell. Cell types that are differentiatedinclude adipocytes, fibroblasts, myocytes, cardiomyocytes, endothelium,neurons, glia, blood cells, megakaryocytes, lymphocytes, macrophages,neutrophils, eosinophils, basophils, mast cells, leukocytes,granulocytes, keratinocytes, chondrocytes, osteoblasts, osteoclasts,hepatocytes, and cells of the endocrine or exocrine glands.

Depending on the particular target HIF-1α RNA sequence and the dose ofdsRNA agent material delivered, this process may provide partial orcomplete loss of function for the HIF-1αRNA. A reduction or loss of RNAlevels or expression (either HIF-1α RNA expression or encodedpolypeptide expression) in at least 50%, 60%, 70%, 80%, 90%, 95% or 99%or more of targeted cells is exemplary Inhibition of HIF-1α RNA levelsor expression refers to the absence (or observable decrease) in thelevel of HIF-1α RNA or HIF-1α RNA-encoded protein. Specificity refers tothe ability to inhibit the HIF-1α RNA without manifest effects on othergenes of the cell. The consequences of inhibition can be confirmed byexamination of the outward properties of the cell or organism or bybiochemical techniques such as RNA solution hybridization, nucleaseprotection, Northern hybridization, reverse transcription, geneexpression monitoring with a microarray, antibody binding, enzyme linkedimmunosorbent assay (ELISA), Western blotting, radioimmunoassay (RIA),other immunoassays, and fluorescence activated cell analysis (FACS)Inhibition of target HIF-1α RNA sequence(s) by the dsRNA agents of theinvention also can be measured based upon the effect of administrationof such dsRNA agents upon development/progression of a HIF-1α-associateddisease or disorder, e.g., tumor formation, growth, metastasis, etc.,either in vivo or in vitro. Treatment and/or reductions in tumor orcancer cell levels can include halting or reduction of growth of tumoror cancer cell levels or reductions of, e.g., 10%, 20%, 30%, 40%, 50%,60%, 70%, 80%, 90%, 95% or 99% or more, and can also be measured inlogarithmic terms, e.g., 10-fold, 100-fold, 1000-fold, 10⁵-fold,10⁶-fold, 10⁷-fold reduction in cancer cell levels could be achieved viaadministration of the dsRNA agents of the invention to cells, a tissue,or a subject.

For RNA-mediated inhibition in a cell line or whole organism, expressiona reporter or drug resistance gene whose protein product is easilyassayed can be measured. Such reporter genes include acetohydroxyacidsynthase (AHAS), alkaline phosphatase (AP), beta galactosidase (LacZ),beta glucoronidase (GUS), chloramphenicol acetyltransferase (CAT), greenfluorescent protein (GFP), horseradish peroxidase (HRP), luciferase(Luc), nopaline synthase (NOS), octopine synthase (OCS), and derivativesthereof. Multiple selectable markers are available that conferresistance to ampicillin, bleomycin, chloramphenicol, gentamycin,hygromycin, kanamycin, lincomycin, methotrexate, phosphinothricin,puromycin, and tetracyclin. Depending on the assay, quantitation of theamount of gene expression allows one to determine a degree of inhibitionwhich is greater than 10%, 33%, 50%, 90%, 95% or 99% as compared to acell not treated according to the present invention.

Lower doses of injected material and longer times after administrationof RNA silencing agent may result in inhibition in a smaller fraction ofcells (e.g., at least 10%, 20%, 50%, 75%, 90%, or 95% of targetedcells). Quantitation of gene expression in a cell may show similaramounts of inhibition at the level of accumulation of target HIF-1α RNAor translation of target protein. As an example, the efficiency ofinhibition may be determined by assessing the amount of gene product inthe cell; RNA may be detected with a hybridization probe having anucleotide sequence outside the region used for the inhibitory dsRNA, ortranslated polypeptide may be detected with an antibody raised againstthe polypeptide sequence of that region.

The dsRNA agent may be introduced in an amount which allows delivery ofat least one copy per cell. Higher doses (e.g., at least 5, 10, 100, 500or 1000 copies per cell) of material may yield more effectiveinhibition; lower doses may also be useful for specific applications.

Pharmaceutical Compositions

In certain embodiments, the present invention provides for apharmaceutical composition comprising the dsRNA agent of the presentinvention. The dsRNA agent sample can be suitably formulated andintroduced into the environment of the cell by any means that allows fora sufficient portion of the sample to enter the cell to induce genesilencing, if it is to occur. Many formulations for dsRNA are known inthe art and can be used so long as the dsRNA gains entry to the targetcells so that it can act. See, e.g., U.S. published patent applicationNos. 2004/0203145 A1 and 2005/0054598 A1. For example, the dsRNA agentof the instant invention can be formulated in buffer solutions such asphosphate buffered saline solutions, liposomes, micellar structures, andcapsids. Formulations of dsRNA agent with cationic lipids can be used tofacilitate transfection of the dsRNA agent into cells. For example,cationic lipids, such as lipofectin (U.S. Pat. No. 5,705,188), cationicglycerol derivatives, and polycationic molecules, such as polylysine(published PCT International Application WO 97/30731), can be used.Suitable lipids include Oligofectamine, Lipofectamine (LifeTechnologies), NC388 (Ribozyme Pharmaceuticals, Inc., Boulder, Colo.),or FuGene 6 (Roche) all of which can be used according to themanufacturer's instructions.

Such compositions typically include the nucleic acid molecule and apharmaceutically acceptable carrier. As used herein the language“pharmaceutically acceptable carrier” includes saline, solvents,dispersion media, coatings, antibacterial and antifungal agents,isotonic and absorption delaying agents, and the like, compatible withpharmaceutical administration. Supplementary active compounds can alsobe incorporated into the compositions.

A pharmaceutical composition is formulated to be compatible with itsintended route of administration. Examples of routes of administrationinclude parenteral, e.g., intravenous, intradermal, subcutaneous, oral(e.g., inhalation), transdermal (topical), transmucosal, and rectaladministration. Solutions or suspensions used for parenteral,intradermal, or subcutaneous application can include the followingcomponents: a sterile diluent such as water for injection, salinesolution, fixed oils, polyethylene glycols, glycerine, propylene glycolor other synthetic solvents; antibacterial agents such as benzyl alcoholor methyl parabens; antioxidants such as ascorbic acid or sodiumbisulfite; cHeLating agents such as ethylenediaminetetraacetic acid;buffers such as acetates, citrates or phosphates and agents for theadjustment of tonicity such as sodium chloride or dextrose. pH can beadjusted with acids or bases, such as hydrochloric acid or sodiumhydroxide. The parenteral preparation can be enclosed in ampoules,disposable syringes or multiple dose vials made of glass or plastic.

Pharmaceutical compositions suitable for injectable use include sterileaqueous solutions (where water soluble) or dispersions and sterilepowders for the extemporaneous preparation of sterile injectablesolutions or dispersion. For intravenous administration, suitablecarriers include physiological saline, bacteriostatic water, CremophorEL™. (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In allcases, the composition must be sterile and should be fluid to the extentthat easy syringability exists. It should be stable under the conditionsof manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, andliquid polyetheylene glycol, and the like), and suitable mixturesthereof. The proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.Prevention of the action of microorganisms can be achieved by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, it will be preferable to include isotonic agents, for example,sugars, polyalcohols such as manitol, sorbitol, sodium chloride in thecomposition. Prolonged absorption of the injectable compositions can bebrought about by including in the composition an agent which delaysabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the activecompound in the required amount in a selected solvent with one or acombination of ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the active compound into a sterile vehicle, which containsa basic dispersion medium and the required other ingredients from thoseenumerated above. In the case of sterile powders for the preparation ofsterile injectable solutions, the preferred methods of preparation arevacuum drying and freeze-drying which yields a powder of the activeingredient plus any additional desired ingredient from a previouslysterile-filtered solution thereof.

Oral compositions generally include an inert diluent or an ediblecarrier. For the purpose of oral therapeutic administration, the activecompound can be incorporated with excipients and used in the form oftablets, troches, or capsules, e.g., gelatin capsules. Oral compositionscan also be prepared using a fluid carrier for use as a mouthwash.Pharmaceutically compatible binding agents, and/or adjuvant materialscan be included as part of the composition. The tablets, pills,capsules, troches and the like can contain any of the followingingredients, or compounds of a similar nature: a binder such asmicrocrystalline cellulose, gum tragacanth or gelatin; an excipient suchas starch or lactose, a disintegrating agent such as alginic acid,Primogel, or corn starch; a lubricant such as magnesium stearate orSterotes; a glidant such as colloidal silicon dioxide; a sweeteningagent such as sucrose or saccharin; or a flavoring agent such aspeppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, the compounds are delivered in theform of an aerosol spray from pressured container or dispenser whichcontains a suitable propellant, e.g., a gas such as carbon dioxide, or anebulizer. Such methods include those described in U.S. Pat. No.6,468,798.

Systemic administration can also be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.Such penetrants are generally known in the art, and include, forexample, for transmucosal administration, detergents, bile salts, andfusidic acid derivatives. Transmucosal administration can beaccomplished through the use of nasal sprays or suppositories. Fortransdermal administration, the active compounds are formulated intoointments, salves, gels, or creams as generally known in the art.

The compounds can also be prepared in the form of suppositories (e.g.,with conventional suppository bases such as cocoa butter and otherglycerides) or retention enemas for rectal delivery.

The compounds can also be administered by transfection or infectionusing methods known in the art, including but not limited to the methodsdescribed in McCaffrey et al. (2002), Nature, 418(6893), 38-9(hydrodynamic transfection); Xia et al. (2002), Nature Biotechnol.,20(10), 1006-10 (viral-mediated delivery); or Putnam (1996), Am. J.Health Syst. Pharm. 53(2), 151-160, erratum at Am. J. Health Syst.Pharm. 53(3), 325 (1996).

The compounds can also be administered by a method suitable foradministration of nucleic acid agents, such as a DNA vaccine. Thesemethods include gene guns, bio injectors, and skin patches as well asneedle-free methods such as the micro-particle DNA vaccine technologydisclosed in U.S. Pat. No. 6,194,389, and the mammalian transdermalneedle-free vaccination with powder-form vaccine as disclosed in U.S.Pat. No. 6,168,587. Additionally, intranasal delivery is possible, asdescribed in, inter alia, Hamajima et al. (1998), Clin. Immunol.Immunopathol., 88(2), 205-10. Liposomes (e.g., as described in U.S. Pat.No. 6,472,375) and microencapsulation can also be used. Biodegradabletargetable microparticle delivery systems can also be used (e.g., asdescribed in U.S. Pat. No. 6,471,996).

In one embodiment, the active compounds are prepared with carriers thatwill protect the compound against rapid elimination from the body, suchas a controlled release formulation, including implants andmicroencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Suchformulations can be prepared using standard techniques. The materialscan also be obtained commercially from Alza Corporation and NovaPharmaceuticals, Inc. Liposomal suspensions (including liposomestargeted to infected cells with monoclonal antibodies to viral antigens)can also be used as pharmaceutically acceptable carriers. These can beprepared according to methods known to those skilled in the art, forexample, as described in U.S. Pat. No. 4,522,811.

Toxicity and therapeutic efficacy of such compounds can be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., for determining the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between toxic and therapeutic effects isthe therapeutic index and it can be expressed as the ratio LD₅₀/ED₅₀.Compounds which exhibit high therapeutic indices are preferred. Whilecompounds that exhibit toxic side effects may be used, care should betaken to design a delivery system that targets such compounds to thesite of affected tissue in order to minimize potential damage touninfected cells and, thereby, reduce side effects.

The data obtained from the cell culture assays and animal studies can beused in formulating a range of dosage for use in humans. The dosage ofsuch compounds lies preferably within a range of circulatingconcentrations that include the ED₅₀ with little or no toxicity. Thedosage may vary within this range depending upon the dosage formemployed and the route of administration utilized. For a compound usedin the method of the invention, the therapeutically effective dose canbe estimated initially from cell culture assays. A dose may beformulated in animal models to achieve a circulating plasmaconcentration range that includes the IC₅₀ (i.e., the concentration ofthe test compound which achieves a half-maximal inhibition of symptoms)as determined in cell culture. Such information can be used to moreaccurately determine useful doses in humans. Levels in plasma may bemeasured, for example, by high performance liquid chromatography.

As defined herein, a therapeutically effective amount of a nucleic acidmolecule (i.e., an effective dosage) depends on the nucleic acidselected. For instance, single dose amounts of a dsRNA (or, e.g., aconstruct(s) encoding for such dsRNA) in the range of approximately 1 pgto 1000 mg may be administered; in some embodiments, 10, 30, 100, or1000 pg, or 10, 30, 100, or 1000 ng, or 10, 30, 100, or 1000 μg, or 10,30, 100, or 1000 mg may be administered. In some embodiments, 1-5 g ofthe compositions can be administered. The compositions can beadministered one from one or more times per day to one or more times perweek; including once every other day. The skilled artisan willappreciate that certain factors may influence the dosage and timingrequired to effectively treat a subject, including but not limited tothe severity of the disease or disorder, previous treatments, thegeneral health and/or age of the subject, and other diseases present.Moreover, treatment of a subject with a therapeutically effective amountof a nucleic acid (e.g., dsRNA), protein, polypeptide, or antibody caninclude a single treatment or, preferably, can include a series oftreatments.

The nucleic acid molecules of the invention can be inserted intoexpression constructs, e.g., viral vectors, retroviral vectors,expression cassettes, or plasmid viral vectors, e.g., using methodsknown in the art, including but not limited to those described in Xia etal., (2002), supra. Expression constructs can be delivered to a subjectby, for example, inhalation, orally, intravenous injection, localadministration (see U.S. Pat. No. 5,328,470) or by stereotacticinjection (see e.g., Chen et al. (1994), Proc. Natl. Acad. Sci. USA, 91,3054-3057). The pharmaceutical preparation of the delivery vector caninclude the vector in an acceptable diluent, or can comprise a slowrelease matrix in which the delivery vehicle is imbedded. Alternatively,where the complete delivery vector can be produced intact fromrecombinant cells, e.g., retroviral vectors, the pharmaceuticalpreparation can include one or more cells which produce the genedelivery system.

The expression constructs may be constructs suitable for use in theappropriate expression system and include, but are not limited toretroviral vectors, linear expression cassettes, plasmids and viral orvirally-derived vectors, as known in the art. Such expression constructsmay include one or more inducible promoters, RNA Pol III promotersystems such as U6 snRNA promoters or H1 RNA polymerase III promoters,or other promoters known in the art. The constructs can include one orboth strands of the siRNA. Expression constructs expressing both strandscan also include loop structures linking both strands, or each strandcan be separately transcribed from separate promoters within the sameconstruct. Each strand can also be transcribed from a separateexpression construct, e.g., Tuschl (2002, Nature Biotechnol 20:500-505).

It can be appreciated that the method of introducing dsRNA agents intothe environment of the cell will depend on the type of cell and the makeup of its environment. For example, when the cells are found within aliquid, one preferable formulation is with a lipid formulation such asin lipofectamine and the dsRNA agents can be added directly to theliquid environment of the cells. Lipid formulations can also beadministered to animals such as by intravenous, intramuscular, orintraperitoneal injection, or orally or by inhalation or other methodsas are known in the art. When the formulation is suitable foradministration into animals such as mammals and more specificallyhumans, the formulation is also pharmaceutically acceptable.Pharmaceutically acceptable formulations for administeringoligonucleotides are known and can be used. In some instances, it may bepreferable to formulate dsRNA agents in a buffer or saline solution anddirectly inject the formulated dsRNA agents into cells, as in studieswith oocytes. The direct injection of dsRNA agent duplexes may also bedone. For suitable methods of introducing dsRNA (e.g., DsiRNA agents),see U.S. published patent application No. 2004/0203145 A1.

Suitable amounts of a dsRNA agent must be introduced and these amountscan be empirically determined using standard methods. Typically,effective concentrations of individual dsRNA agent species in theenvironment of a cell will be 50 nanomolar or less, 10 nanomolar orless, or compositions in which concentrations of 1 nanomolar or less canbe used. In another embodiment, methods utilizing a concentration of 200picomolar or less, 100 picomolar or less, 50 picomolar or less, 20picomolar or less, and even a concentration of 10 picomolar or less, 5picomolar or less, 2 picomolar or less or 1 picomolar or less can beused in many circumstances.

The method can be carried out by addition of the dsRNA agentcompositions to an extracellular matrix in which cells can live providedthat the dsRNA agent composition is formulated so that a sufficientamount of the dsRNA agent can enter the cell to exert its effect. Forexample, the method is amenable for use with cells present in a liquidsuch as a liquid culture or cell growth media, in tissue explants, or inwhole organisms, including animals, such as mammals and especiallyhumans.

The level or activity of a HIF-1α RNA can be determined by a suitablemethod now known in the art or that is later developed. It can beappreciated that the method used to measure a target RNA and/or theexpression of a target RNA can depend upon the nature of the target RNA.For example, where the target HIF-1α RNA sequence encodes a protein, theterm “expression” can refer to a protein or the HIF-1α RNA/transcriptderived from the HIF-1α gene (either genomic or of exogenous origin). Insuch instances the expression of the target HIF-1αRNA can be determinedby measuring the amount of HIF-1α RNA/transcript directly or bymeasuring the amount of HIF-1α protein. Protein can be measured inprotein assays such as by staining or immunoblotting or, if the proteincatalyzes a reaction that can be measured, by measuring reaction rates.All such methods are known in the art and can be used. Where targetHIF-1α RNA levels are to be measured, art-recognized methods fordetecting RNA levels can be used (e.g., RT-PCR, Northern Blotting,etc.). In targeting HIF-1α RNAs with the dsRNA agents of the instantinvention, it is also anticipated that measurement of the efficacy of adsRNA agent in reducing levels of HIF-1α RNA or protein in a subject,tissue, in cells, either in vitro or in vivo, or in cell extracts canalso be used to determine the extent of reduction of HIF-1α-associatedphenotypes (e.g., disease or disorders, e.g., cancer or tumor formation,growth, metastasis, spread, etc.). The above measurements can be made oncells, cell extracts, tissues, tissue extracts or other suitable sourcematerial.

The determination of whether the expression of a HIF-1α RNA has beenreduced can be by a suitable method that can reliably detect changes inRNA levels. Typically, the determination is made by introducing into theenvironment of a cell undigested dsRNA such that at least a portion ofthat dsRNA agent enters the cytoplasm, and then measuring the level ofthe target RNA. The same measurement is made on identical untreatedcells and the results obtained from each measurement are compared.

The dsRNA agent can be formulated as a pharmaceutical composition whichcomprises a pharmacologically effective amount of a dsRNA agent andpharmaceutically acceptable carrier. A pharmacologically ortherapeutically effective amount refers to that amount of a dsRNA agenteffective to produce the intended pharmacological, therapeutic orpreventive result. The phrases “pharmacologically effective amount” and“therapeutically effective amount” or simply “effective amount” refer tothat amount of an RNA effective to produce the intended pharmacological,therapeutic or preventive result. For example, if a given clinicaltreatment is considered effective when there is at least a 20% reductionin a measurable parameter associated with a disease or disorder, atherapeutically effective amount of a drug for the treatment of thatdisease or disorder is the amount necessary to effect at least a 20%reduction in that parameter.

Suitably formulated pharmaceutical compositions of this invention can beadministered by means known in the art such as by parenteral routes,including intravenous, intramuscular, intraperitoneal, subcutaneous,transdermal, airway (aerosol), rectal, vaginal and topical (includingbuccal and sublingual) administration. In some embodiments, thepharmaceutical compositions are administered by intravenous orintraparenteral infusion or injection.

In general, a suitable dosage unit of dsRNA will be in the range of0.001 to 0.25 milligrams per kilogram body weight of the recipient perday, or in the range of 0.01 to 20 micrograms per kilogram body weightper day, or in the range of 0.001 to 5 micrograms per kilogram of bodyweight per day, or in the range of 1 to 500 nanograms per kilogram ofbody weight per day, or in the range of 0.01 to 10 micrograms perkilogram body weight per day, or in the range of 0.10 to 5 microgramsper kilogram body weight per day, or in the range of 0.1 to 2.5micrograms per kilogram body weight per day. A pharmaceuticalcomposition comprising the dsRNA can be administered once daily.However, the therapeutic agent may also be dosed in dosage unitscontaining two, three, four, five, six or more sub-doses administered atappropriate intervals throughout the day. In that case, the dsRNAcontained in each sub-dose must be correspondingly smaller in order toachieve the total daily dosage unit. The dosage unit can also becompounded for a single dose over several days, e.g., using aconventional sustained release formulation which provides sustained andconsistent release of the dsRNA over a several day period. Sustainedrelease formulations are well known in the art. In this embodiment, thedosage unit contains a corresponding multiple of the daily dose.Regardless of the formulation, the pharmaceutical composition mustcontain dsRNA in a quantity sufficient to inhibit expression of thetarget gene in the animal or human being treated. The composition can becompounded in such a way that the sum of the multiple units of dsRNAtogether contain a sufficient dose.

Data can be obtained from cell culture assays and animal studies toformulate a suitable dosage range for humans. The dosage of compositionsof the invention lies within a range of circulating concentrations thatinclude the ED₅₀ (as determined by known methods) with little or notoxicity. The dosage may vary within this range depending upon thedosage form employed and the route of administration utilized. For acompound used in the method of the invention, the therapeuticallyeffective dose can be estimated initially from cell culture assays. Adose may be formulated in animal models to achieve a circulating plasmaconcentration range of the compound that includes the IC₅₀ (i.e., theconcentration of the test compound which achieves a half-maximalinhibition of symptoms) as determined in cell culture. Such informationcan be used to more accurately determine useful doses in humans. Levelsof dsRNA in plasma may be measured by standard methods, for example, byhigh performance liquid chromatography.

The pharmaceutical compositions can be included in a kit, container,pack, or dispenser together with instructions for administration.

Methods of Treatment

The present invention provides for both prophylactic and therapeuticmethods of treating a subject at risk of (or susceptible to) a diseaseor disorder caused, in whole or in part, by HIF-1α(e.g., misregulationand/or elevation of HIF-1α transcript and/or HIF-1α protein levels), ortreatable via selective targeting of HIF-1α.

“Treatment”, or “treating” as used herein, is defined as the applicationor administration of a therapeutic agent (e.g., a dsRNA agent or vectoror transgene encoding same) to a patient, or application oradministration of a therapeutic agent to an isolated tissue or cell linefrom a patient, who has the disease or disorder, a symptom of disease ordisorder or a predisposition toward a disease or disorder, with thepurpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate,improve or affect the disease or disorder, the symptoms of the diseaseor disorder, or the predisposition toward disease.

In one aspect, the invention provides a method for preventing in asubject, a disease or disorder as described above (including, e.g.,prevention of the commencement of transforming events within a subjectvia inhibition of HIF-1α expression), by administering to the subject atherapeutic agent (e.g., a dsRNA agent or vector or transgene encodingsame). Subjects at risk for the disease can be identified by, forexample, one or a combination of diagnostic or prognostic assays asdescribed herein. Administration of a prophylactic agent can occur priorto the detection of, e.g., cancer in a subject, or the manifestation ofsymptoms characteristic of the disease or disorder, such that thedisease or disorder is prevented or, alternatively, delayed in itsprogression.

Another aspect of the invention pertains to methods of treating subjectstherapeutically, i.e., altering the onset of symptoms of the disease ordisorder. These methods can be performed in vitro (e.g., by culturingthe cell with the dsRNA agent) or, alternatively, in vivo (e.g., byadministering the dsRNA agent to a subject).

With regards to both prophylactic and therapeutic methods of treatment,such treatments may be specifically tailored or modified, based onknowledge obtained from the field of pharmacogenomics.“Pharmacogenomics”, as used herein, refers to the application ofgenomics technologies such as gene sequencing, statistical genetics, andgene expression analysis to drugs in clinical development and on themarket. More specifically, the term refers the study of how a patient'sgenes determine his or her response to a drug (e.g., a patient's “drugresponse phenotype”, or “drug response genotype”). Thus, another aspectof the invention provides methods for tailoring an individual'sprophylactic or therapeutic treatment with either the target HIF-1α RNAmolecules of the present invention or target HIF-1α RNA modulatorsaccording to that individual's drug response genotype. Pharmacogenomicsallows a clinician or physician to target prophylactic or therapeutictreatments to patients who will most benefit from the treatment and toavoid treatment of patients who will experience toxic drug-related sideeffects.

Therapeutic agents can be tested in a selected animal model. Forexample, a dsRNA agent (or expression vector or transgene encoding same)as described herein can be used in an animal model to determine theefficacy, toxicity, or side effects of treatment with said agent.Alternatively, an agent (e.g., a therapeutic agent) can be used in ananimal model to determine the mechanism of action of such an agent.

Models Useful to Evaluate the Down-Regulation of HIF-1α mRNA Levels andExpression

Cell Culture

The dsRNA agents of the invention can be tested for cleavage activity invivo, for example, using the following procedure. The nucleotidesequences within the HIF-1α cDNA targeted by the dsRNA agents of theinvention are shown in the above HIF-1α sequences.

The dsRNA reagents of the invention can be tested in cell culture usingHeLa or other mammalian cells to determine the extent of HIF-1α RNA andHIF-1α protein inhibition. In certain embodiments, DsiRNA reagents(e.g., see FIG. 1, and above-recited structures) are selected againstthe HIF-1α target as described herein. HIF-1α RNA inhibition is measuredafter delivery of these reagents by a suitable transfection agent to,for example, cultured HeLa cells or other transformed or non-transformedmammalian cells in culture. Relative amounts of target HIF-1α RNA aremeasured versus actin or other appropriate control using real-time PCRmonitoring of amplification (e.g., ABI 7700 TAQMAN®). A comparison ismade to a mixture of oligonucleotide sequences made to unrelated targetsor to a randomized DsiRNA control with the same overall length andchemistry, but randomly substituted at each position, or simply toappropriate vehicle-treated or untreated controls. Primary and secondarylead reagents are chosen for the target and optimization performed.After a transfection agent concentration is chosen, a RNA time-course ofinhibition is performed with the lead DsiRNA molecule.

TAQMAN® (Real-Time PCR Monitoring of Amplification) and LightcyclerQuantification of mRNA

Total RNA is prepared from cells following DsiRNA delivery, for example,using Ambion Rnaqueous 4-PCR purification kit for large scaleextractions, or Promega SV96 for 96-well assays. For Taqman analysis,dual-labeled probes are synthesized with, for example, the reporter dyesFAM or VIC covalently linked at the 5′-end and the quencher dyeTAMHIF-1αA conjugated to the 3′-end. PCR amplifications are performedon, for example, an ABI PRISM 7700 Sequence detector using 50 uLreactions consisting of 10 uL total RNA, 100 nM forward primer, 100 mMreverse primer, 100 nM probe, 1× TaqMan PCR reaction buffer (PE-AppliedBiosystems), 5.5 mM MgCl2, 100 uM each dATP, dCTP, dGTP and dTTP, 0.2 URNase Inhibitor (Promega), 0.025 U AmpliTaq Gold (PE-Applied Biosystems)and 0.2 U M-MLV Reverse Transcriptase (Promega). The thermal cyclingconditions can consist of 30 minutes at 48° C., 10 minutes at 95° C.,followed by 40 cycles of 15 seconds at 95° C. and 1 minute at 60° C.Quantitation of target HIF-1α mRNA level is determined relative tostandards generated from serially diluted total cellular RNA (300, 100,30, 10 ng/r×n) and normalizing to, for example, 36B4 mRNA in eitherparallel or same tube TaqMan reactions.

Western Blotting

Cellular protein extracts can be prepared using a standard micropreparation technique (for example using RIPA buffer), or preferably, byextracting nuclear proteins by a method such as the NE-PER Nuclear andCytoplasmic Extraction kit (Thermo-Fisher Scientific). Cellular proteinextracts are run on 4-12% Tris-Glycine polyacrylamide gel andtransferred onto membranes. Non-specific binding can be blocked byincubation, for example, with 5% non-fat milk for 1 hour followed byprimary antibody for 16 hours at 4° C. Following washes, the secondaryantibody is applied, for example (1:10,000 dilution) for 1 hour at roomtemperature and the signal detected on a VersaDoc imaging system

In several cell culture systems, cationic lipids have been shown toenhance the bioavailability of oligonucleotides to cells in culture(Bennet, et al., 1992, Mol. Pharmacology, 41, 1023-1033). In oneembodiment, dsRNA molecules of the invention are complexed with cationiclipids for cell culture experiments. dsRNA and cationic lipid mixturesare prepared in serum-free OptimMEM (InVitrogen) immediately prior toaddition to the cells. OptiMEM is warmed to room temperature (about20-25° C.) and cationic lipid is added to the final desiredconcentration. dsRNA molecules are added to OptiMEM to the desiredconcentration and the solution is added to the diluted dsRNA andincubated for 15 minutes at room temperature. In dose responseexperiments, the RNA complex is serially diluted into OptiMEM prior toaddition of the cationic lipid.

Animal Models

The efficacy of anti-HIF-1α dsRNA agents may be evaluated in an animalmodel. Animal models of cancer and/or proliferative diseases,conditions, or disorders as are known in the art can be used forevaluation of the efficacy, potency, toxicity, etc. of anti-HIF-1αdsRNAs. Suitable animal models of proliferative disease include, e.g.,transgenic rodents (e.g., mice, rats) bearing gain of functionproto-oncogenes (e.g., Myc, Src) and/or loss of function of tumoursuppressor proteins (e.g., p53, Rb) or rodents that have been exposed toradiation or chemical mutagens that induce DNA changes that facilitateneoplastic transformation. Many such animal models are commerciallyavailable, for example, from The Jackson Laboratory, Bar Harbor, Me.,USA. These animal models may be used as a source cells or tissue forassays of the compositions of the invention. Such models can also beused or adapted for use for pre-clinical evaluation of the efficacy ofdsRNA compositions of the invention in modulating HIF-1α gene expressiontoward therapeutic use.

As in cell culture models, the most HIF-1α relevant mouse tumorxenografts are those derived from cancer cells that express HIF-1αproteins. Xenograft mouse models of cancer relevant to study of theanti-tumor effect of modulating HIF-1α have been described by variousgroups (e.g., Welsh et al., Mol Cancer Ther. 2004; 3(3):233-244,“Antitumor Activity and pharmacodynamic properties of PX-478, aninhibitor of hypoxia-inducible factor-1α”; Chen et al., Am J Pathol2003, 162:1283-1291, “Dominant-Negative Hypoxia-Inducible Factor-1aReduces Tumorigenicity of Pancreatic Cancer Cells through theSuppression of Glucose Metabolisom”). Use of these models hasdemonstrated that inhibition of HIF-1α expression by anti-HIF-1α agentscauses inhibition of tumor growth in animals.

Such models can be used in evaluating the efficacy of dsRNA molecules ofthe invention to inhibit HIF-1α levels, expression, tumor/cancerformation, growth, spread, development of other HIF-1α-associatedphenotypes, diseases or disorders, etc. These models and others cansimilarly be used to evaluate the safety/toxicity and efficacy of dsRNAmolecules of the invention in a pre-clinical setting.

Specific examples of animal model systems useful for evaluation of theHIF-1α-targeting dsRNAs of the invention include wild-type mice, andorthotopic or subcutaneous Panc-1, MiaPaCa, DU-145, OvCar-3, MCF-7, orSHP-77 tumor model mice. In an exemplary in vivo experiment, dsRNAs ofthe invention are tail vein injected into such mouse models at dosesranging from 1 to 10 mg/kg or, alternatively, repeated doses areadministered at single-dose IC₅₀ levels, and organs (e.g., prostate,liver, kidney, lung, pancreas, colon, skin, spleen, bone marrow, lymphnodes, mammary fat pad, etc.) are harvested 24 hours afteradministration of the final dose. Such organs are then evaluated formouse and/or human HIF-1α levels, depending upon the model used.Duration of action can also be examined at, e.g., 1, 4, 7, 14, 21 ormore days after final dsRNA administration.

The practice of the present invention employs, unless otherwiseindicated, conventional techniques of chemistry, molecular biology,microbiology, recombinant DNA, genetics, immunology, cell biology, cellculture and transgenic biology, which are within the skill of the art.See, e.g., Maniatis et al., 1982, Molecular Cloning (Cold Spring HarborLaboratory Press, Cold Spring Harbor, N.Y.); Sambrook et al., 1989,Molecular Cloning, 2nd Ed. (Cold Spring Harbor Laboratory Press, ColdSpring Harbor, N.Y.); Sambrook and Russell, 2001, Molecular Cloning, 3rdEd. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.);Ausubel et al., 1992), Current Protocols in Molecular Biology (JohnWiley & Sons, including periodic updates); Glover, 1985, DNA Cloning(IRL Press, Oxford); Anand, 1992; Guthrie and Fink, 1991; Harlow andLane, 1988, Antibodies, (Cold Spring Harbor Laboratory Press, ColdSpring Harbor, N.Y.); Jakoby and Pastan, 1979; Nucleic AcidHybridization (B. D. Hames & S. J. Higgins eds. 1984); Transcription AndTranslation (B. D. Hames & S. J. Higgins eds. 1984); Culture Of AnimalCells (R. I. Freshney, Alan R. Liss, Inc., 1987); Immobilized Cells AndEnzymes (IRL Press, 1986); B. Perbal, A Practical Guide To MolecularCloning (1984); the treatise, Methods In Enzymology (Academic Press,Inc., N.Y.); Gene Transfer Vectors For Mammalian Cells (J. H. Miller andM. P. Calos eds., 1987, Cold Spring Harbor Laboratory); Methods InEnzymology, Vols. 154 and 155 (Wu et al. eds.), Immunochemical MethodsIn Cell And Molecular Biology (Mayer and Walker, eds., Academic Press,London, 1987); Handbook Of Experimental Immunology, Volumes I-IV (D. M.Weir and C. C. Blackwell, eds., 1986); Riott, Essential Immunology, 6thEdition, Blackwell Scientific Publications, Oxford, 1988; Hogan et al.,Manipulating the Mouse Embryo, (Cold Spring Harbor Laboratory Press,Cold Spring Harbor, N.Y., 1986); Westerfield, M., The zebrafish book. Aguide for the laboratory use of zebrafish (Danio rerio), (4th Ed., Univ.of Oregon Press, Eugene, 2000).

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, suitable methods andmaterials are described below. All publications, patent applications,patents, and other references mentioned herein are incorporated byreference in their entirety. In case of conflict, the presentspecification, including definitions, will control. In addition, thematerials, methods, and examples are illustrative only and not intendedto be limiting.

EXAMPLES

The present invention is described by reference to the followingExamples, which are offered by way of illustration and are not intendedto limit the invention in any manner. Standard techniques well known inthe art or the techniques specifically described below were utilized.

Example 1: Preparation of Double-Stranded RNA Oligonucleotides

Oligonucleotide Synthesis and Purification

DsiRNA molecules can be designed to interact with various sites in theRNA message, for example, target sequences within the RNA sequencesdescribed herein. In presently exemplified agents, 378 human targetHIF-1α sequences and 72 mouse target HIF-1α sequences were selected forevaluation (258 of the 378 human target HIF-1α sites were predicted tobe conserved with corresponding sites in the mouse HIF-1α transcriptsequence). The sequences of one strand of the DsiRNA molecules werecomplementary to the target HIF-1α site sequences described above. TheDsiRNA molecules were chemically synthesized using methods describedherein. Generally, DsiRNA constructs were synthesized using solid phaseoligonucleotide synthesis methods as described for 19-23mer siRNAs (seefor example Usman et al., U.S. Pat. Nos. 5,804,683; 5,831,071;5,998,203; 6,117,657; 6,353,098; 6,362,323; 6,437,117; 6,469,158;Scaringe et al., U.S. Pat. Nos. 6,111,086; 6,008,400; 6,111,086).

Individual RNA strands were synthesized and HPLC purified according tostandard methods (Integrated DNA Technologies, Coralville, Iowa). Forexample, RNA oligonucleotides were synthesized using solid phasephosphoramidite chemistry, deprotected and desalted on NAP-5 columns(Amersham Pharmacia Biotech, Piscataway, N.J.) using standard techniques(Damha and Olgivie, 1993, Methods Mol Biol 20: 81-114; Wincott et al.,1995, Nucleic Acids Res 23: 2677-84). The oligomers were purified usingion-exchange high performance liquid chromatography (IE-HPLC) on anAmersham Source 15Q column (1.0 cm×25 cm; Amersham Pharmacia Biotech,Piscataway, N.J.) using a 15 min step-linear gradient. The gradientvaries from 90:10 Buffers A:B to 52:48 Buffers A:B, where Buffer A is100 mM Tris pH 8.5 and Buffer B is 100 mM Tris pH 8.5, 1 M NaCl. Sampleswere monitored at 260 nm and peaks corresponding to the full-lengtholigonucleotide species are collected, pooled, desalted on NAP-5columns, and lyophilized.

The purity of each oligomer was determined by capillary electrophoresis(CE) on a Beckman PACE 5000 (Beckman Coulter, Inc., Fullerton, Calif.).The CE capillaries had a 100 μm inner diameter and contains ssDNA 100RGel (Beckman-Coulter). Typically, about 0.6 nmole of oligonucleotide wasinjected into a capillary, run in an electric field of 444 V/cm anddetected by UV absorbance at 260 nm. Denaturing Tris-Borate-7 M-urearunning buffer was purchased from Beckman-Coulter. Oligoribonucleotideswere obtained that are at least 90% pure as assessed by CE for use inexperiments described below. Compound identity was verified bymatrix-assisted laser desorption ionization time-of-flight (MALDI-TOF)mass spectroscopy on a Voyager DE™ Biospectometry Work Station (AppliedBiosystems, Foster City, Calif.) following the manufacturer'srecommended protocol. Relative molecular masses of all oligomers wereobtained, often within 0.2% of expected molecular mass.

Preparation of Duplexes

Single-stranded RNA (ssRNA) oligomers were resuspended, e.g., at 100 μMconcentration in duplex buffer consisting of 100 mM potassium acetate,30 mM HEPES, pH 7.5. Complementary sense and antisense strands weremixed in equal molar amounts to yield a final solution of, e.g., 50 μMduplex. Samples were heated to 100° C. for 5′ in RNA buffer (IDT) andallowed to cool to room temperature before use. Double-stranded RNA(dsRNA) oligomers were stored at −20° C. Single-stranded RNA oligomerswere stored lyophilized or in nuclease-free water at −80° C.

Nomenclature

For consistency, the following nomenclature has been employed in theinstant specification. Names given to duplexes indicate the length ofthe oligomers and the presence or absence of overhangs. A “25/27” is anasymmetric duplex having a 25 base sense strand and a 27 base antisensestrand with a 2-base 3′-overhang. A “27/25” is an asymmetric duplexhaving a 27 base sense strand and a 25 base antisense strand.

Cell Culture and RNA Transfection

HeLa cells were obtained from ATCC and maintained in DMEM (HyClone)supplemented with 10% fetal bovine serum (HyClone) at 37° C. under 5%CO₂. HEPA1-6 cells were obtained from ATCC and maintained in DMEM(HyClone) supplemented with 10% fetal bovine serum (HyClone) at 37° C.under 5% CO₂. For RNA transfections, cells were transfected with DsiRNAsas indicated at a final concentration of 1 nM, 0.3 nM or 0.1 nM usingLipofectamine™ RNAiMAX (Invitrogen) and following manufacturer'sinstructions. Briefly, for 0.1 nM transfections, e.g., of Example 8below, an aliquot of stock solution of each DsiRNA was mixed withOpti-MEM I (Invitrogen) and Lipofectamine™ RNAiMAX to reach a volume of200 μL. The resulting 200 μL mix was added per well into duplicateindividual wells of 24 well plates and incubated for 20 min at RT toallow DsiRNA:Lipofectamine™ RNAiMAX complexes to form. Meanwhile, targetcells were trypsinized and resuspended in medium. Finally, 300 μL of thecell suspension were added to each well (final volume 500 μL) and plateswere placed into the incubator for 24 hours.

Assessment of HIF-1α Inhibition

HIF-1α target gene knockdown was determined by qRT-PCR, with valuesnormalized to HPRT and SFRS9 housekeeping genes (or, in Example 8 below,to HPRT only), and to transfections with control DsiRNAs and/or mocktransfection controls.

RNA Isolation and Analysis

Media was aspirated, and total RNA was extracted using the SV96 kit(Promega). Approximately 100 ng of total RNA was reverse-transcribedusing SuperscriptII, Oligo dT, and random hexamers followingmanufacturer's instructions. Typically, one-sixth of the resulting cDNAwas analyzed by qPCR using primers and probes specific for both theHIF-1α gene and for the human genes HPRT-1 and SFRS9. An ABI 7700 wasused for the amplification reactions. Each sample was tested intriplicate. Relative Hif-1α RNA levels were normalized to HPRT1 andSFRS9 RNA levels and compared with RNA levels obtained in mocktransfection control samples. For Example 8 below, approximately 200 ngof total RNA was reverse-transcribed using Transcriptor First StrandcDNA Synthesis Kit (Roche) and random hexamers following manufacturer'sinstructions. Typically, on-fifteenth of the resulting cDNA was analyzedby qPCR using primers and probes specific for both the Hif-1α gene andfor the human gene HPRT-1. A Bio-Rad CFX96 was used for theamplification reactions. Each sample was tested in duplicate. RelativeHif-1α RNA levels were normalized to HPRT1 RNA levels and compared withRNA levels obtained in mock transfection control samples.

Example 2: DsiRNA Inhibition of HIF-1α —Primary Screen

DsiRNA molecules targeting HIF-1α were designed and synthesized asdescribed above and tested in HeLa cells for inhibitory efficacy. Fortransfection, annealed DsiRNAs were mixed with the transfection reagent(Lipofectamine™ RNAiMAX, Invitrogen) in a volume of 50 μl/well andincubated for 20 minutes at room temperature. The HeLa (human) orHEPA1-6 (mouse) cells were trypsinized, resuspended in media, and addedto wells (100 uL per well) to give a final DsiRNA concentration of 1 nMin a volume of 150 μl. Each DsiRNA transfection mixture was added to 3wells for triplicate DsiRNA treatments. Cells were incubated at 37° C.for 24 hours in the continued presence of the DsiRNA transfectionmixture. At 24 hours, RNA was prepared from each well of treated cells.The supernatants with the transfection mixtures were first removed anddiscarded, then the cells were lysed and RNA prepared from each well.Target HIF-1α RNA levels following treatment were evaluated by qRT-PCRfor the HIF-1α target gene, with values normalized to those obtained forcontrols. Triplicate data was averaged and the % error determined foreach treatment. Normalized data were graphed and the reduction of targetmRNA by active DsiRNAs in comparison to controls was determined.

HIF-1α targeting DsiRNAs examined for HIF-1α inhibitory efficacy in aprimary phase of testing are indicated in Tables 8 and 9 below. In thisexample, 450 asymmetric DsiRNAs (tested DsiRNAs possessed a 25/27merstructure) were constructed and tested for HIF-1α inhibitory efficacy inhuman HeLa and mouse HEPA1-6 cells incubated in the presence of suchDsiRNAs at a concentration of 1 nM. The 450 asymmetric DsiRNAs testedincluded DsiRNAs selected from Tables 2 and 4 above, where sequences andstructures of these tested asymmetric DsiRNAs are shown (in above Tables2 and 4, underlined nucleotide residues indicate 2′-O-methyl modifiedresidues, ribonucleotide residues are shown as UPPER CASE, anddeoxyribonucleotide residues are shown as lower case).

Assay of the 450 HIF-1α targeting DsiRNAs in human HeLa and mouseHEPA1-6 cells at 1 nM revealed the following HIF-1α inhibitoryefficacies, presented in Tables 8 and 9. HIF-1α levels were determinedusing qPCR assays positioned at indicated locations within the HIF-1αtranscript (for human HeLa cell experiments, paired qPCR assays wereperformed and are indicated as “Hs HIF-1α 815-1008” (MAX) and “Hs HIF-1α2690-2866” (FAM); for mouse HEPA1-6 cell experiments, paired qPCR assayswere performed and are indicated as “Mm HIF-1α 1055-1223” (MAX) and “MmHIF-1α 2463-2593” (FAM)).

TABLE 8 HIF-1α Inhibitory Efficacy of DsiRNAs Assayed at 1 nM in HumanHeLa Cells DsiRNA Name Human HIF- % Remaining % Remaining (Human HIF-1α1α Target HIF-1α mRNA ± HIF-1α mRNA ± Target Location, Location, MouseHIF- % Error % Error Transcript Transcript 1α Target (Assay: Hs (Assay:Hs HIF- Variant 1) Variant 2 Location HIF-1α 815-1008) 1α 2690-2866)HIF-1α-81 81 m103 131 ± 7.1 114.8 ± 4.1  HIF-1α-83 83 m105 119.7 ± 6.3 112.2 ± 4   HIF-1α-85 85 m107 146.6 ± 13.9 168.4 ± 13.6 HIF-1α-87 87m109 103.6 ± 7.2  112.2 ± 10.2 HIF-1α-89 89 m111 122.8 ± 3.9  119.4 ±2.1  HIF-1α-123 123 N/A 105.9 ± 11.4 103.5 ± 13.5 HIF-1α-124 124 N/A101.5 ± 5.4  92.4 ± 5.1 HIF-1α-126 126 N/A 100.4 ± 5.5   101 ± 4.1HIF-1α-130 130 N/A  96.1 ± N/A 136.7 ± N/A HIF-1α-131 131 N/A 113.3 ±7   98.1 ± 4.5 HIF-1α-147 147 N/A 110.9 ± 3.9  135.8 ± 6.2  HIF-1α-265265 N/A 99.2 ± 8.8 99.9 ± 5.2 HIF-1α-267 267 N/A 42.7 ± 4.9 51.3 ± 6.5HIF-1α-268 268 N/A 60.2 ± 8   91.8 ± 6.9 HIF-1α-292 292 N/A   80 ± 6.6 101 ± 7.2 HIF-1α-319 319 N/A 34.4 ± 7   34.4 ± 8.1 HIF-1α-322 322 N/A53.1 ± 1.9 69.9 ± 2   HIF-1α-324 324 N/A 86.9 ± 3.3 54.5 ± 4.5HIF-1α-327 327 N/A 111.4 ± 11.5 96.9 ± 7.7 HIF-1α-329 329 N/A 85.1 ± 5.4104.9 ± 13.5 HIF-1α-330 330 N/A 82.9 ± 5.2 75.7 ± 6.3 HIF-1α-331 331 N/A  103 ± 10.9 106.8 ± 12.8 HIF-1α-342 342 N/A 130.1 ± 4.8  132.7 ± 4.1 HIF-1α-344 344 N/A 117.6 ± 3.1  73.8 ± 7   HIF-1α-346 346 N/A 96.5 ± 8.692.9 ± 8.9 HIF-1α-359 359 N/A 54.6 ± 9.8 47.6 ± 7   HIF-1α-403 403 N/A26.8 ± 4.6   29 ± 3.8 HIF-1α-422 422 N/A 133.7 ± 16.1 138.9 ± 16.7HIF-1α-427 427 m446   121 ± 10.5 128.3 ± 11.1 HIF-1α-429 429 m448 146.2± 3.4  132.7 ± 10.9 HIF-1α-448 448 N/A  23.9 ± 14.1 31.3 ± 9.9HIF-1α-455 455 N/A 47.4 ± 9.1 56.2 ± 12  HIF-1α-469 469 m488   27 ± 3.827.3 ± 4.4 HIF-1α-471 471 m490 17.1 ± 5.2 17.5 ± 3.1 HIF-1α-473 473 m492 13.8 ± 10.3 16.4 ± 9.6 HIF-1α-475 475 m494 10.2 ± 7.3  22.2 ± 13.6HIF-1α-525 525 N/A 18.1 ± 7.1  13.5 ± 12.6 HIF-1α-528 528 m547   33 ±2.6 42.1 ± 5.2 HIF-1α-530 530 m549 21.1 ± 3.3 23.1 ± 3.3 HIF-1α-532 532m551 25.7 ± 5   27.7 ± 6.5 HIF-1α-534 534 m553  18.4 ± 12.1 21.7 ± 6.9HIF-1α-536 536 m555  24.4 ± N/A   26 ± N/A HIF-1α-538 538 m557 49.8 ±6   47.9 ± 5.2 HIF-1α-540 540 m559 23.6 ± 2.3 25.1 ± 2.4 HIF-1α-542 542m561 17.4 ± 9.9  25.4 ± 12.7 HIF-1α-544 544 m563 17.2 ± 5.4 24.1 ± 3.9HIF-1α-546 546 m565 16.6 ± 8.7 20 ± 7 HIF-1α-548 548 m567 18.4 ± 8.620.9 ± 6.3 HIF-1α-550 550 m569 18.5 ± 5.6  16.9 ± 11.4 HIF-1α-562 562N/A 14.3 ± 9.6 16.9 ± 4.8 HIF-1α-642 642 N/A  13.2 ± 10.1 14.3 ± 9.9HIF-1α-644 644 N/A 19.3 ± 9.7 19.7 ± 4.8 HIF-1α-645 645 N/A  25.7 ± 15.145.2 ± 5.4 HIF-1α-665 665 N/A 43.8 ± 15  29.9 ± 5.7 HIF-1α-691 691 N/A  15 ± 6.9 14.8 ± 6.6 HIF-1α-707 707 N/A  13.3 ± 12.6  13.2 ± 19.7HIF-1α-711 711 N/A   9 ± 7.6  9.7 ± 13.4 HIF-1α-713 713 N/A 10.7 ± 6.513 ± 7 HIF-1α-715 715 N/A  7.3 ± 10.8  15.4 ± 16.2 HIF-1α-717 717 N/A10.5 ± 12   13.8 ± 14.6 HIF-1α-756 756 N/A 15.2 ± 9.2 14.6 ± 8.4HIF-1α-790 790 N/A 10.8 ± 5.9 11.9 ± 4.2 HIF-1α-793 793 m812 12.8 ± 7.614.5 ± 6.8 HIF-1α-824 824 m843 14.3 ± 8   15.6 ± 6   HIF-1α-826 826 m84551.6 ± 6.5 56.1 ± 6.5 HIF-1α-828 828 m847  18.6 ± 17.9 34.4 ± 7.8HIF-1α-830 830 m849 64.2 ± 8.9   82 ± 11.2 HIF-1α-832 832 m851 33.2 ±8.4 40.7 ± 4.1 HIF-1α-834 834 m853   16 ± 5.4 22.4 ± 2.5 HIF-1α-836 836m855  58.4 ± 10.1  38.5 ± 16.5 HIF-1α-838 838 m857   16 ± 7.6 17.9 ± 3.6HIF-1α-840 840 m859 18.1 ± 3.4 21.8 ± 4.3 HIF-1α-842 842 m861 17.5 ± 3.120.7 ± 3.9 HIF-1α-844 844 m863  9.3 ± 18.2  24.1 ± 19.2 HIF-1α-846 846m865   15 ± 1.1 19.9 ± 5.5 HIF-1α-848 848 m867 13.8 ± 4.2 19.9 ± 9.8HIF-1α-850 850 m869  9.7 ± 3.9 13.7 ± 2.6 HIF-1α-852 852 m871 14.2 ± 4.314.5 ± 2.3 HIF-1α-921 921 N/A    7 ± 16.7  15 ± 11 HIF-1α-925 925 m944 8.9 ± 7.6 11.9 ± 5.5 HIF-1α-927 927 m946 62.5 ± 3.5 62.8 ± 2.3HIF-1α-1029 1029 m1048 41.1 ± 8.4 42.8 ± 7.4 HIF-1α-1031 1031 m1050 29.1± 4.6 45.8 ± 4.4 HIF-1α-1033 1033 m1052  28.7 ± 18.9  39.5 ± 15.4HIF-1α-1035 1035 m1054  7.9 ± 5.8 13.9 ± 4   HIF-1α-1037 1037 m1056 30.4± 3.3 33.6 ± 4   HIF-1α-1039 1039 m1058  45.6 ± 13.2  48.5 ± 16.4HIF-1α-1041 1041 m1060 12.7 ± 9.8 15.4 ± 7.5 HIF-1α-1043 1043 m1062 54.4± 2.5 54.5 ± 3.1 HIF-1α-1045 1045 m1064 40.2 ± 4.5 46.5 ± 2.4HIF-1α-1074 1074 N/A   18 ± 9.5  13.6 ± 11.9 HIF-1α-1075 1075 N/A  17.6± 17.3   35 ± 13.3 HIF-1α-1077 1077 N/A  10.8 ± 12.4  9.7 ± 9.2HIF-1α-1084 1084 m1103    6 ± 16.9 13.4 ± 7.9 HIF-1α-1086 1086 m1105 33.7 ± 16.4  43.1 ± 18.5 HIF-1α-1088 1088 m1107 10.5 ± 7   13.1 ± 6.2HIF-1α-1090 1090 m1109  5.7 ± 7.3 10 ± 5 HIF-1α-1092 1092 m1111  N/A ±N/A  N/A ± N/A HIF-1α-1094 1094 m1113 11.7 ± 1.2   18 ± 4.9 HIF-1α-10961096 m1115 17.9 ± 6.7 20.8 ± 7.1 HIF-1α-1120 1120 m1139  12.9 ± 20.6 15.8 ± 10.7 HIF-1α-1122 1122 m1141    6 ± 15.3 21.5 ± 9.3 HIF-1α-11241124 m1143 29.2 ± 6.7 35.2 ± 4   HIF-1α-1126 1126 m1145 67.6 ± 5     59± 5.7 HIF-1α-1128 1128 m1147 7.1 ± 9  10.5 ± 8   HIF-1α-1130 1130 m114915.3 ± 0.8 15.4 ± 3.3 HIF-1α-1132 1132 m1151 26.7 ± 2.7 27.2 ± 2.2HIF-1α-1166 1166 N/A 13.1 ± 6.1 13.8 ± 4.5 HIF-1α-1174 1174 N/A 30.4 ±9.3  40.3 ± 10.1 HIF-1α-1243 1243 m1262  6.8 ± 3.8   8 ± 2.7 HIF-1α-12451245 m1264  11.9 ± 20.1  13.8 ± 16.2 HIF-1α-1247 1247 m1266  9.3 ± 10.7 16.4 ± 12.3 HIF-1α-1249 1249 m1268 15.3 ± 9.2 18.1 ± 9.6 HIF-1α-12511251 m1270 67.3 ± 7.7 57.6 ± 8.9 HIF-1α-1253 1253 m1272 39.3 ± 6.5 39.5± 4.9 HIF-1α-1255 1255 m1274 41.5 ± 1.5 40.8 ± 9.1 HIF-1α-1257 1257m1276 31.8 ± 3   31.8 ± 3.2 HIF-1α-1262 1262 N/A 15.1 ± 7.9 15.2 ± 7.9HIF-1α-1265 1265 N/A  17.8 ± 10.3  18.7 ± 17.8 HIF-1α-1268 1268 N/A 24.4± 6.1 25.9 ± 3.6 HIF-1α-1271 1271 N/A 16.2 ± 6.4 18.7 ± 8.8 HIF-1α-12781278 m1297 28.5 ± 3.6 23.7 ± 2   HIF-1α-1280 1280 m1299  16.3 ± 11.3 15.2 ± 10.3 HIF-1α-1282 1282 m1301  8.9 ± 16.5  16.5 ± 15.9 HIF-1α-13031303 m1322  5.1 ± 13.3   8 ± 8.5 HIF-1α-1305 1305 m1324  8.7 ± 15.6   12± 10.3 HIF-1α-1307 1307 m1326 33.7 ± 5.6 32.8 ± 2.3 HIF-1α-1309 1309m1328  52 ± 24  42.7 ± 24.9 HIF-1α-1311 1311 m1330   48 ± 3.3 40.9 ± 4.7HIF-1α-1313 1313 m1332  35.9 ± 12.7 31.4 ± 8.2 HIF-1α-1315 1315 m1334 6.9 ± 7.2 13.2 ± 4.1 HIF-1α-1317 1317 m1336  29.3 ± 12.7  57.8 ± 11.9HIF-1α-1319 1319 m1338  21.9 ± 10.1   20 ± 25.7 HIF-1α-1321 1321 m1340  28 ± 6.6  26.3 ± 10.7 HIF-1α-1323 1323 m1342 30.2 ± 8.1 26.9 ± 8  HIF-1α-1325 1325 m1344 16.1 ± 11  25.1 ± 9   HIF-1α-1327 1327 m1346 56.4± 5.8 44.2 ± 4.3 HIF-1α-1329 1329 m1348  4.3 ± 20.5  8.4 ± 8.9HIF-1α-1331 1331 m1350 30.9 ± 8.8  25.8 ± 11.3 HIF-1α-1333 1333 m135212.1 ± 4.3 21.6 ± 13  HIF-1α-1335 1335 m1354  11.2 ± 14.5  14.3 ± 17.9HIF-1α-1337 1337 m1356  9.6 ± 4.1  9.5 ± 3.3 HIF-1α-1339 1339 m1358 11.8± 5.9   11 ± 5.1 HIF-1α-1341 1341 m1360 31.7 ± 8.3 23.9 ± 6.3HIF-1α-1343 1343 m1362 19.8 ± 4.7 18.8 ± 2.8 HIF-1α-1345 1345 m1364 10.7 ± 17.7 12.4 ± 8.3 HIF-1α-1347 1347 m1366 29.4 ± 11  31.4 ± 7.7HIF-1α-1349 1349 m1368  7.1 ± 12.4 14.4 ± 9.6 HIF-1α-1351 1351 m137013.8 ± 10  16.2 ± 5.6 HIF-1α-1353 1353 m1372 16.6 ± 7.3 24.4 ± 8.4HIF-1α-1355 1355 m1374  5.5 ± 7.3  6.9 ± 6.9 HIF-1α-1357 1357 m1376   13± 11.6  18.1 ± 16.5 HIF-1α-1359 1359 m1378   9 ± 4.6 10.3 ± 4  HIF-1α-1361 1361 m1380  12.1 ± 20.2  13.7 ± 13.5 HIF-1α-1363 1363 m1382 5.1 ± 7.3  6.5 ± 3.9 HIF-1α-1365 1365 m1384  7.8 ± 7.1  17.7 ± 13.9HIF-1α-1367 1367 m1386  20.2 ± 10.3  23.5 ± 10.3 HIF-1α-1369 1369 m1388 7.7 ± 8.6  10.2 ± 24.3 HIF-1α-1371 1371 m1390 17.7 ± 4.5 18.2 ± 6.4HIF-1α-1373 1373 m1392  6.4 ± 5.9 10.4 ± 3.4 HIF-1α-1375 1375 m1394  6.2± 3.6  7.8 ± 1.1 HIF-1α-1377 1377 m1396 16.9 ± 5.2   18 ± 4.2HIF-1α-1379 1379 m1398  6.8 ± 4.5 9.9 ± 6  HIF-1α-1381 1381 m1400  5.5 ±16.7  10.7 ± 12.1 HIF-1α-1383 1383 m1402  13.6 ± 11.4  14.6 ± 11.9HIF-1α-1385 1385 m1404  4.3 ± 5.5  7.5 ± 3.5 HIF-1α-1387 1387 m1406 10.1± 7.4   12 ± 7.2 HIF-1α-1456 1456 m1475  5.7 ± 13.8  9.1 ± 21.2HIF-1α-1458 1458 m1477  5.3 ± 7.3  6.7 ± 6.1 HIF-1α-1460 1460 m1479 17.3± 4.9 18.9 ± 5.8 HIF-1α-1462 1462 m1481  6.4 ± 2.3  7.9 ± 7.3HIF-1α-1464 1464 m1483   24 ± 19.3 29.8 ± 4.2 HIF-1α-1466 1466 m1485 11.3 ± 18.5   17 ± 19.1 HIF-1α-1468 1468 m1487  9.2 ± 15.6  7.6 ± 8.1HIF-1α-1470 1470 m1489   7 ± 6.3  9.2 ± 7.6 HIF-1α-1472 1472 m1491  6.8± 19.7  26.2 ± 31.9 HIF-1α-1474 1474 m1493  7.4 ± 4.4 12.5 ± 6.6HIF-1α-1476 1476 m1495  13.1 ± 11.9 15.1 ± 9.7 HIF-1α-1478 1478 m1497  5 ± 9.5  6.8 ± 3.3 HIF-1α-1480 1480 m1499   24 ± 21.6  32.1 ± 24.7HIF-1α-1482 1482 m1501 18.2 ± 6.6   28 ± 6.3 HIF-1α-1519 1519 m1538  7.2± 12.4  5.4 ± 6.8 HIF-1α-1552 1552 m1571 10.8 ± 3.9 12.6 ± 4.8HIF-1α-1572 1572 N/A   10 ± 1.3 11.2 ± 3.1 HIF-1α-1648 1648 N/A  16.6 ±11.4  16.3 ± 10.5 HIF-1α-1709 1709 N/A 26.7 ± 5.1 30.3 ± 6.2 HIF-1α-17141714 m1733 15.8 ± 4.6 28.3 ± 4.1 HIF-1α-1786 1786 N/A 47.3 ± 5.3 48.7 ±1.9 HIF-1α-1804 1804 m1820 10.2 ± 5.2 11.6 ± 5.7 HIF-1α-1806 1806 m182246.6 ± 6.8 46.5 ± 7.6 HIF-1α-1808 1808 m1824 29.7 ± 6.3 32.4 ± 4.6HIF-1α-1810 1810 m1826  35.2 ± 30.1  46.2 ± 13.4 HIF-1α-1814 1814 N/A70.4 ± 1.5 77.3 ± 3.2 HIF-1α-1845 1845 N/A 14.6 ± 8.6 12.3 ± 7.5HIF-1α-1936 1936 m1952  20.2 ± 17.2   30 ± 13.4 HIF-1α-1938 1938 m195416.9 ± 5.3 10.6 ± 3.9 HIF-1α-1940 1940 m1956 23.6 ± 7.7 26.6 ± 8.1HIF-1α-1942 1942 m1958 46.5 ± 6.8  60.8 ± 15.8 HIF-1α-1944 1944 m196019.3 ± 3.2 22.7 ± 4.2 HIF-1α-1946 1946 m1962 15.3 ± 8.1 17.9 ± 6.1HIF-1α-1977 1977 N/A 22.3 ± 2.6   22 ± 3.3 HIF-1α-1985 1985 N/A  14.2 ±23.2   8 ± 6.5 HIF-1α-2034 2034 N/A 10.3 ± 6.7 9.9 ± 6.7 HIF-1α-21162116 m2174   14 ± 3.8 16.4 ± 4.6 HIF-1α-2118 2118 m2176  10.4 ± 10.7 9.8 ± 10.6 HIF-1α-2120 2120 m2178  10.8 ± 10.5   15 ± 4.3 HIF-1α-21222122 m2180  28.5 ± 11.3 23.2 ± 5.5 HIF-1α-2161 2161 m2219 10.8 ± 7.615.9 ± 4.1 HIF-1α-2185 2185 N/A   42 ± 6.5 48.8 ± 8.4 HIF-1α-2187 2187N/A 17.5 ± 2.9 32.2 ± 8.7 HIF-1α-2290 2290 N/A  9.8 ± 3.8  9.6 ± 5.5HIF-1α-2326 2326 N/A 20.5 ± 4.6 25.2 ± 4   HIF-1α-2452 2452 m2504  9.4 ±8.6  24.8 ± 42.5 HIF-1α-2555 2555 N/A 10.6 ± 1.9   11 ± 5.5 HIF-1α-25772577 N/A   12 ± 9.7 12.3 ± 7.5 HIF-1α-2584 2584 m2633 17.6 ± 5.8 23.4 ±4.8 HIF-1α-2586 2586 m2635  18.8 ± 10.4 24.8 ± 8.9 HIF-1α-2618 N/A N/A15.7 ± 3.6  9.2 ± 5.7 HIF-1α-2705 N/A m2754 19.9 ± 5.6 12.6 ± 4.8HIF-1α-2730 N/A N/A 17.1 ± 5.4 11.3 ± 7.2 HIF-1α-2796 2669 m2845 10.6 ±3.7   10 ± 7.5 HIF-1α-2798 2671 m2847 12.6 ± 9.7  8.4 ± 2.6 HIF-1α-28002673 m2849 14.7 ± 4.2 16.2 ± 4.3 HIF-1α-2802 2675 m2851   13 ± 10.9 10.2± 8.3 HIF-1α-2823 2696 m2872 33.5 ± 6.8 39.5 ± 3.7 HIF-1α-2844 2717m2893  19.5 ± 11.7 33.4 ± 4.5 HIF-1α-2846 2719 m2895   35 ± 2.1 40.9 ±3.9 HIF-1α-2848 2721 m2897 33.5 ± 6.1 38.9 ± 4.1 HIF-1α-2850 2723 m2899  29 ± 15.2  33.3 ± 11.3 HIF-1α-2852 2725 m2901  10.5 ± 14.2  7.7 ± 6.7HIF-1α-2854 2727 m2903 28.5 ± 3.6 32 ± 5 HIF-1α-2856 2729 m2905 10.3 ±2.6  6.2 ± 7.8 HIF-1α-2858 2731 m2907 15.2 ± 8.7 14.8 ± 6.8 HIF-1α-28602733 m2909 11.7 ± 5.4  16.4 ± 18.5 HIF-1α-2862 2735 m2911  9.2 ± 2.5 7.8 ± 5.6 HIF-1α-2864 2737 m2913  9.2 ± 5.7  6.1 ± 10.7 HIF-1α-28662739 m2915 20.8 ± 7.4 19.2 ± 6.7 HIF-1α-2868 2741 m2917   12 ± 8.9 13.4± 1.5 HIF-1α-2870 2743 m2919  10.8 ± 14.2  9.4 ± 12.5 HIF-1α-2872 2745m2921 18.1 ± 5.6 17.6 ± 4.6 HIF-1α-2874 2747 m2923  9.1 ± 4.5  8.9 ± 4.7HIF-1α-2876 2749 m2925 11.5 ± 7.6  14.2 ± 29.1 HIF-1α-2878 2751 m2927 9.8 ± 7.2  6.7 ± 3.6 HIF-1α-2880 2753 m2929  6.9 ± 12.3  4.2 ± 14.8HIF-1α-2882 2755 m2931  9.7 ± 3.9  8.3 ± 7.2 HIF-1α-2884 2757 m2933 11.7± 9   12 ± 9 HIF-1α-2886 2759 m2935  7.1 ± 6.4  5.5 ± 8.1 HIF-1α-28882761 m2937   35 ± 3.5 40.4 ± 4.6 HIF-1α-2890 2763 m2939 11.2 ± 9.1 12.5± 9.4 HIF-1α-2892 2765 m2941 12.4 ± 5.8 17.6 ± 4.5 HIF-1α-2895 2768 N/A 7.6 ± 17.3    6 ± 17.3 HIF-1α-2906 2779 N/A 13.8 ± 6.3 12.1 ± 6.1HIF-1α-2910 2783 N/A  10.7 ± 17.4  8.5 ± 19.9 HIF-1α-2919 2792 N/A 74 ±5  66.6 ± 13.2 HIF-1α-2925 2798 N/A  14.7 ± 22.2 13.6 ± 9.9 HIF-1α-29332806 m3042 15.7 ± 5     14 ± 2.5 HIF-1α-2935 2808 m3044 17.2 ± 3.5 14.6± 4.8 HIF-1α-2963 2836 m3063 16.2 ± 5.7 11.7 ± 3.8 HIF-1α-2965 2838m3065 16.5 ± 8.3 14.8 ± 6.8 HIF-1α-2970 2843 N/A 13.8 ± 4.3  9.7 ± 3.3HIF-1α-2986 2859 m3086 33.3 ± 7.2 32.7 ± 9.2 HIF-1α-2988 2861 m3088 19.5± 7.3 14.1 ± 3.4 HIF-1α-2990 2863 m3090 25.3 ± 6.5 23.8 ± 8.5HIF-1α-2992 2865 m3092 25.9 ± 1.2  26.8 ± 12.8 HIF-1α-2994 2867 m309435.2 ± 5.2 30.2 ± 6.5 HIF-1α-2996 2869 m3096 35.3 ± 4.8 16.8 ± 3.1HIF-1α-2998 2871 m3098  23.6 ± N/A  13.3 ± N/A HIF-1α-3000 2873 m3100  35 ± 23.6   24 ± 8.3 HIF-1α-3002 2875 m3102 34.6 ± 7.1 24.7 ± 7.4HIF-1α-3004 2877 m3104 23.5 ± 4.1 22.4 ± 4.2 HIF-1α-3055 2928 N/A 24.4 ±3.3 21.2 ± 8   HIF-1α-3065 2938 N/A 16.4 ± 6   15.2 ± 7.6 HIF-1α-30672940 N/A 14.9 ± 8.2   13 ± 5.8 HIF-1α-3068 2941 N/A 19.8 ± 2.8 15.3 ±2.9 HIF-1α-3077 2950 N/A   37 ± 3.9  31.1 ± 10.6 HIF-1α-3081 2954 N/A27.5 ± 7.3 23.8 ± 9.3 HIF-1α-3088 2961 N/A  22.6 ± 10.5 18.6 ± 7.7HIF-1α-3093 2966 N/A 35.2 ± 7.7 23.6 ± 9.4 HIF-1α-3110 2983 N/A 21.1 ±8.3 16.9 ± 8.3 HIF-1α-3167 3040 m3257 17.6 ± 5.4 13.3 ± 7.6 HIF-1α-31693042 m3259 17.2 ± 19  15.3 ± 2.9 HIF-1α-3171 3044 m3261 15.1 ± 3.6 10.1± 4.9 HIF-1α-3173 3046 m3263 24.6 ± 4.8 20.1 ± 4   HIF-1α-3175 3048m3265   30 ± 5.4 27.1 ± 5.9 HIF-1α-3177 3050 m3267 43.5 ± 5.8 50.6 ± 8.8HIF-1α-3179 3052 m3269 108.2 ± 9.6  142.4 ± 9.3  HIF-1α-3215 3088 N/A 28.8 ± 12.7 30.7 ± 12  HIF-1α-3241 3114 N/A 24.1 ± 8.2 19.8 ± 3.8HIF-1α-3274 3147 m3362 25.8 ± 3.3 24.7 ± 5.9 HIF-1α-3276 3149 m3364 24.8± 3   23.6 ± 2.6 HIF-1α-3278 3151 m3366 21.8 ± 6.5  19.6 ± 13.5HIF-1α-3280 3153 m3368  24.6 ± 10.1 18.6 ± 7   HIF-1α-3292 3165 N/A 35.3± 7.4  38.2 ± 17.1 HIF-1α-3310 3183 N/A 18.5 ± 7.7 14.8 ± 8.1HIF-1α-3358 3231 m3444 23.8 ± 9.8 11.8 ± 10  HIF-1α-3360 3233 m3446 26.7 ± 11.8 19.1 ± 9.1 HIF-1α-3362 3235 m3448  15.7 ± 25.1  15.6 ± 14.2HIF-1α-3364 3237 m3450 25.5 ± 7.7 21.1 ± 6.9 HIF-1α-3366 3239 m3452   24± 8.1 21.9 ± 5.5 HIF-1α-3368 3241 m3454   25 ± 7.1  19.5 ± 10.7HIF-1α-3374 3247 N/A 27.6 ± 9.1  28.1 ± 15.5 HIF-1α-3425 3298 N/A  18.9± 18.7 32.8 ± 9.2 HIF-1α-3426 3299 m3511  17.4 ± 10.3  16.6 ± 13.5HIF-1α-3428 3301 m3513   28 ± 2.5 24.8 ± 3.2 HIF-1α-3430 3303 m3515   20± 2.7 16.2 ± 4.2 HIF-1α-3442 3315 N/A 22.4 ± 5.8 20.3 ± 3   HIF-1α-34483321 m3530 21.2 ± 3   16.4 ± 3.1 HIF-1α-3450 3323 m3532 20.3 ± 2.7 17.4± 4.3 HIF-1α-3465 3338 N/A  23.2 ± 11.5   23 ± 3.8 HIF-1α-3493 3366 N/A26.9 ± 3.6 26.3 ± 4.7 HIF-1α-3529 3402 N/A 28.9 ± 6.8   23 ± 5.6HIF-1α-3546 3419 m3620  15.7 ± 12.3  11.8 ± 11.3 HIF-1α-3557 3430 N/A39.3 ± 3.2   33 ± 4.3 HIF-1α-3592 3465 m3666  24.5 ± 12.6 21.1 ± 8  HIF-1α-3594 3467 m3668 21.9 ± 2.2 19.7 ± 1.8 HIF-1α-3596 3469 m3670   13± 16.5   22 ± 6.5 HIF-1α-3598 3471 m3672 15.3 ± 9.2 12.4 ± 9  HIF-1α-3600 3473 m3674  9.8 ± 2.1  7.3 ± 4.3 HIF-1α-3602 3475 m3676 12.4± 7.4 10.9 ± 8.6 HIF-1α-3604 3477 m3678  23.4 ± 10.4 22 ± 8 HIF-1α-36063479 m3680 11.6 ± 8.2  9.6 ± 7.8 HIF-1α-3608 3481 m3682 14.9 ± 9.8 15.9± 8.2 HIF-1α-3608 3481 m3682  19.4 ± 12.3 15.1 ± 12  HIF-1α-3610 3483m3684 14.9 ± 1     14 ± 2.5 HIF-1α-3612 3485 m3686 13.5 ± 1.8 15.8 ± 15 HIF-1α-3614 3487 m3688   32 ± 6.9 27.2 ± 6.4 HIF-1α-3616 3489 m3690 18.4± 4.5 15.5 ± 5.6 HIF-1α-3640 3513 N/A   19 ± 3.4 16.2 ± 4.1 HIF-1α-36463519 N/A 18.3 ± 9.2 17.1 ± 8.3 HIF-1α-3651 3524 N/A 24.4 ± 10   21.7 ±10.4 HIF-1α-3670 3543 N/A   19 ± 13.2 16.1 ± 8.2 HIF-1α-3743 3616 N/A 21.3 ± 13.3 16.3 ± 8.4 HIF-1α-3745 3618 N/A 24.1 ± 6.3 16.5 ± 4.1HIF-1α-3746 3619 N/A 32.3 ± 5    24.9 ± 13.5 HIF-1α-3748 3621 N/A  31.2± 11.5 26.4 ± 9.4 HIF-1α-3749 3622 N/A 36.7 ± 8.2 33.6 ± 9.3 HIF-1α-37543627 N/A  21.5 ± 13.1  15.5 ± 12.1 HIF-1α-3757 3630 N/A 28.7 ± 6   30.3± 6.6 HIF-1α-3791 3664 N/A   20 ± 4.9  25.1 ± 14.7 HIF-1α-3830 3703 N/A19.7 ± 4.3 19.1 ± 5.5 HIF-1α-3861 3734 m3927 14.8 ± 4.2 12.4 ± 2.7HIF-1α-3863 3736 m3929 20.6 ± 4.1   20 ± 4.2 HIF-1α-3865 3738 m3931 13.7 ± 14.8 11.9 ± 12  HIF-1α-3867 3740 m3933  13.8 ± 10.2 13.3 ± 9.4HIF-1α-3869 3742 m3935 18.6 ± 2.9   16 ± 1.6 HIF-1α-3871 3744 m3937 15.3 ± 11.4 17.4 ± 8.2 HIF-1α-3873 3746 m3939 15.6 ± 3.9 13.4 ± 5.4HIF-1α-3875 3748 m3941 25.2 ± 8.8 17.6 ± 7.3 HIF-1α-3877 3750 m3943 15.9± 4.9 11.2 ± 3.6 HIF-1α-3880 3753 N/A   18 ± 7.8 13.8 ± 5.2 HIF-1α-39163789 m3981  12.8 ± 10.3  12.9 ± 12.7 HIF-1α-3918 3791 m3983 20.6 ± 11 16.1 ± 10  HIF-1α-3920 3793 m3985 29.7 ± 6.2 17.8 ± 2.6 HIF-1α-3922 3795m3987 19.7 ± 9.1 13.9 ± 7.3 HIF-1α-3924 3797 m3989  29.1 ± 10.8  14.4 ±18.4 HIF-1α-3926 3799 m3991 21.7 ± 6     15 ± 4.3 HIF-1α-3928 3801 m399319.8 ± 6.8 15.1 ± 5.2 HIF-1α-3930 3803 m3995  12.2 ± 10.3  8.9 ± 7.5HIF-1α-3961 3834 N/A 24.2 ± 7.9 22.9 ± 9.4 HIF-1α-3980 3853 N/A 17.9 ±4.1 12.1 ± 7.4 HIF-1α-3999 3872 N/A 22 ± 4   19 ± 3.3 HIF-1α-4000 3873N/A 21.1 ± 6.8 27.6 ± 6.3 HIF-1α-4001 3874 N/A  29.1 ± 10.8  14.2 ± 11.5HIF-1α-4003 3876 N/A 22.3 ± 4.6 23.7 ± 2.2 HIF-1α-4004 3877 N/A 18.7 ±4.9 17.5 ± 2.5 HIF-1α-4005 3878 N/A 16.5 ± 7.1 13.9 ± 9.2 HIF-1α-40063879 N/A 24.5 ± 5.8 18.3 ± 6.4 HIF-1α-4007 3880 N/A   28 ± 15.9 21.1 ±2.9 HIF-1α-4008 3881 N/A 21.6 ± 8.4 18.6 ± 8.3 HIF-1α-4009 3882 N/A 23.3± 6.9 17.8 ± 6   HIF-1α-4010 3883 N/A 18.9 ± 4.1 17.2 ± 6.2 HIF-1α-40123885 N/A  19.8 ± 10.2 10.7 ± 2   HIF-1α-4055 3928 m4119   22 ± 5.2 25.6± 3.3 HIF-1α-4057 3930 m4121  19.1 ± 12.5 16.1 ± 8.8 HIF-1α-4059 3932m4123  29.4 ± 10.6 19.1 ± 4.4 HIF-1α-4061 3934 m4125 35.4 ± 3.3 31.4 ±4   HIF-1α-4063 3936 m4127  54.8 ± 10.5 46.1 ± 5.6 HIF-1α-4065 3938m4129 49.3 ± 8.5 36.6 ± 8  

TABLE 9 HIF-1α Inhibitory Efficacy of DsiRNAs Assayed at 1 nM in MouseHEPA1-6 Cells % Remaining DsiRNA Name Human HIF- HIF-1α % Remaining(Human HIF-1α 1α Target Mouse HIF-1α mRNA ± % HIF-1α mRNA ± TargetLocation, Location, Target Error (Assay: % Error Transcript TranscriptLocation/ Mm HIF-1α (Assay: Mm Variant 1) Variant 2 DsiRNA Name1055-1223) HIF-1α 2463-2593) HIF-1α-81 81 m103 135.6 ± 5.4  125.9 ± 5.7 HIF-1α-83 83 m105 113.8 ± 5.6  118.1 ± 4.1  HIF-1α-85 85 m107 142.8 ±9.5  153.3 ± 1.2  HIF-1α-87 87 m109 98.9 ± 9    102 ± 5.2 HIF-1α-89 89m111 153.1 ± 5.1  150.8 ± 3.2  HIF-1α-427 427 m446 117.6 ± 10.9 124.5 ±6.9  HIF-1α-429 429 m448 142.5 ± 5   108.6 ± 11.4 HIF-1α-469 469 m48859.8 ± 9.2 55.2 ± 8   HIF-1α-471 471 m490  37.9 ± 14.5  35 ± 16HIF-1α-473 473 m492 23.4 ± 8.9 25.3 ± 4.5 HIF-1α-475 475 m494 40.5 ± 6  49.7 ± 5.2 HIF-1α-528 528 m547 81.6 ± 3.3   77 ± 3.4 HIF-1α-530 530 m549 67.2 ± N/A  62.5 ± N/A HIF-1α-532 532 m551 62 ± 3 59.4 ± 4.3 HIF-1α-534534 m553 54.2 ± 8.1 39.8 ± 9.9 HIF-1α-536 536 m555 81.2 ± 6   74.9 ± 5.8HIF-1α-538 538 m557 83.6 ± 5.8 72.6 ± 7.6 HIF-1α-540 540 m559 59.9 ± 9.554.8 ± 8.1 HIF-1α-542 542 m561   47 ± 5.2   54 ± 10.3 HIF-1α-544 544m563  51.2 ± 10.2 42.7 ± 7.8 HIF-1α-546 546 m565 45.7 ± 9.5 46.8 ± 5.6HIF-1α-548 548 m567  42.8 ± 11.4 40.3 ± 9.8 HIF-1α-550 550 m569 25.9 ±6.3 22.2 ± 8.5 HIF-1α-793 793 m812  59.6 ± 10.9 58.6 ± 8.8 HIF-1α-824824 m843  52.6 ± 17.7 53.6 ± 17  HIF-1α-826 826 m845 53.1 ± 3.3 65.4 ±6.8 HIF-1α-828 828 m847 48.6 ± 5.6  54.6 ± 16.5 HIF-1α-830 830 m849   93± 14.1 127.5 ± 8.6  HIF-1α-832 832 m851 57.9 ± 3.6 64.6 ± 1.1 HIF-1α-834834 m853 38.3 ± 6.1 51.9 ± 5.8 HIF-1α-836 836 m855 70.9 ± 8.5 67.2 ± 5.7HIF-1α-838 838 m857  56.9 ± 11.6 62.9 ± 14  HIF-1α-840 840 m859 54.7 ±9.1 56.8 ± 7   HIF-1α-842 842 m861  38.6 ± 12.2 45.6 ± 9.7 HIF-1α-844844 m863 32.4 ± 8.4 27.6 ± 4.9 HIF-1α-846 846 m865 38.5 ± 11  49.4 ± 4.4HIF-1α-848 848 m867 38.2 ± 7.3  43.1 ± 14.2 HIF-1α-850 850 m869 33.7 ±7.4 39.1 ± 8.4 HIF-1α-852 852 m871 41.3 ± 3.9 40.4 ± 2.6 HIF-1α-925 925m944 66.8 ± 6.7 74.6 ± 2.8 HIF-1α-927 927 m946 87.5 ± 4.1 95 ± 2HIF-1α-1029 1029 m1048 81.2 ± 3.7 88.2 ± 4.2 HIF-1α-1031 1031 m1050 67.4± 6.9 61.9 ± 5.7 HIF-1α-1033 1033 m1052  80.5 ± 10.4 94.1 ± 9.5HIF-1α-1035 1035 m1054   24 ± N/A  26.6 ± N/A HIF-1α-1037 1037 m105674.5 ± 6.8 89.1 ± 7.5 HIF-1α-1039 1039 m1058  83.8 ± 10.4 88.1 ± 3.7HIF-1α-1041 1041 m1060 108.5 ± 4.1  120.6 ± 4.8  HIF-1α-1043 1043 m106286.2 ± 4.9   91 ± 2.5 HIF-1α-1045 1045 m1064   72 ± 8.4 90.5 ± 4.9HIF-1α-1084 1084 m1103 22.7 ± 4.8  25.7 ± 26.6 HIF-1α-1086 1086 m110564.9 ± 9.6  86.9 ± 10.5 HIF-1α-1088 1088 m1107  24.6 ± 15.6  30.7 ± 13.2HIF-1α-1090 1090 m1109  20.6 ± 20.4  24.8 ± 16.4 HIF-1α-1092 1092 m1111 46.5 ± 11.7  71.4 ± 10.4 HIF-1α-1094 1094 m1113 40.8 ± 4   44.9 ± 3.9HIF-1α-1096 1096 m1115 71.8 ± 6.2 86.2 ± 4.6 HIF-1α-1120 1120 m1139 29.2 ± 15.9  35.3 ± 14.4 HIF-1α-1122 1122 m1141  15.1 ± 21.8  9.8 ± 13HIF-1α-1124 1124 m1143 34.8 ± 7.6 47.8 ± 8.4 HIF-1α-1126 1126 m1145 49.8± 2.3 64.1 ± 3.5 HIF-1α-1128 1128 m1147 26.4 ± 7.5 30.8 ± 4.4HIF-1α-1130 1130 m1149 30.5 ± 4.1 37.5 ± 7.6 HIF-1α-1132 1132 m1151 76.1± 1.6 85.9 ± 2.2 HIF-1α-1243 1243 m1262  21.2 ± 11.8   26 ± 11.8HIF-1α-1245 1245 m1264 15.8 ± 9.3  29.8 ± 34.7 HIF-1α-1247 1247 m126624.9 ± 4.9 17.8 ± 2.4 HIF-1α-1249 1249 m1268 23.8 ± 6.7 32.5 ± 4.3HIF-1α-1251 1251 m1270 56.8 ± 3.1 69.1 ± 3.1 HIF-1α-1253 1253 m1272 65.3± 3.4 63.9 ± 2   HIF-1α-1255 1255 m1274 70.5 ± 6.1 80.6 ± 7.4HIF-1α-1257 1257 m1276 76.2 ± 7   89.9 ± 3.4 HIF-1α-1278 1278 m1297 33.5± 1.5 34.9 ± 3.2 HIF-1α-1280 1280 m1299 14.6 ± 2.4 17.8 ± 2.6HIF-1α-1282 1282 m1301  14.3 ± 15.9  16.6 ± 15.3 HIF-1α-1303 1303 m1322 9.6 ± 8.3  13.2 ± 12.6 HIF-1α-1305 1305 m1324  17.7 ± 13.9  25.4 ± 10.5HIF-1α-1307 1307 m1326   38 ± 6.2 48.7 ± 7.4 HIF-1α-1309 1309 m1328 31.7 ± 10.9 53.7 ± 8.1 HIF-1α-1311 1311 m1330 37.1 ± 4.4 45.3 ± 4.3HIF-1α-1313 1313 m1332 32.9 ± 3.1 36.3 ± 3.1 HIF-1α-1315 1315 m1334 11.2± 7.7 20.2 ± 4.6 HIF-1α-1317 1317 m1336   34 ± 8.1 36.9 ± 4.3HIF-1α-1319 1319 m1338 24.9 ± 6.4 32.1 ± 1.8 HIF-1α-1321 1321 m1340 42 ±3 43.9 ± 1.7 HIF-1α-1323 1323 m1342  32.7 ± 13.5 35.4 ± 4.5 HIF-1α-13251325 m1344 17.2 ± 5.2 22.5 ± 5.3 HIF-1α-1327 1327 m1346 54.9 ± 5.6 55.2± 2.3 HIF-1α-1329 1329 m1348 15.3 ± 4.5 15.4 ± 3.8 HIF-1α-1331 1331m1350  38.1 ± 11.5 40.3 ± 7.1 HIF-1α-1333 1333 m1352  15.3 ± 11.8 16.9 ±9.6 HIF-1α-1335 1335 m1354  10.8 ± 10.5 15.6 ± 6.6 HIF-1α-1337 1337m1356 12.6 ± 6.7 15.3 ± 5.9 HIF-1α-1339 1339 m1358 13.3 ± 7.3 16.2 ± 5  HIF-1α-1341 1341 m1360  28.4 ± 13.9 31.3 ± 2.6 HIF-1α-1343 1343 m1362 22.5 ± 9.72  5.1 ± 10.7 HIF-1α-1345 1345 m1364  24.6 ± 11.8  29.1 ±15.4 HIF-1α-1347 1347 m1366 39.3 ± 8.3 48.7 ± 5.2 HIF-1α-1349 1349 m1368 14.3 ± 15.6  16.3 ± 20.7 HIF-1α-1351 1351 m1370  31.1 ± N/A  39.4 ± N/AHIF-1α-1353 1353 m1372 34.5 ± 3.7 37.6 ± 2   HIF-1α-1355 1355 m1374 16.8 ± 10.5 21.7 ± 9.3 HIF-1α-1357 1357 m1376  25.2 ± 16.9  30.7 ± 13.9HIF-1α-1359 1359 m1378 19.9 ± 7.8  21.1 ± 10.8 HIF-1α-1361 1361 m138017.9 ± 7.2 20.9 ± 9.4 HIF-1α-1363 1363 m1382  10.9 ± 14.6  12.1 ± 11.4HIF-1α-1365 1365 m1384 18 ± 2 15.2 ± 4.2 HIF-1α-1367 1367 m1386 26.2 ±5.2 34.9 ± 2.9 HIF-1α-1369 1369 m1388 11.3 ± 8.3  12.9 ± 11.8HIF-1α-1371 1371 m1390 29.5 ± 5.3 35.3 ± 7.5 HIF-1α-1373 1373 m1392 12.2± 2.5   15 ± 4.6 HIF-1α-1375 1375 m1394 13.8 ± 8.2 14.9 ± 6.8HIF-1α-1377 1377 m1396 18.5 ± 4.1 19.6 ± 3.4 HIF-1α-1379 1379 m1398 14.6± 10  18.8 ± 5.1 HIF-1α-1381 1381 m1400  9.1 ± 3.2 8.3 ± 2  HIF-1α-13831383 m1402 18.7 ± 5.7 21.7 ± 3.1 HIF-1α-1385 1385 m1404  6.2 ± 6.9  7.4± 3.9 HIF-1α-1387 1387 m1406  19.1 ± 13.3 20.9 ± 10  HIF-1α-1456 1456m1475 11.2 ± 8.8 12.9 ± 5.3 HIF-1α-1458 1458 m1477  10.4 ± 16.4   11 ±9.6 HIF-1α-1460 1460 m1479 21.3 ± 6.3 21.6 ± 7.3 HIF-1α-1462 1462 m148118.9 ± 9.9 19.1 ± 10  HIF-1α-1464 1464 m1483  28.2 ± 12.2 26 ± 2HIF-1α-1466 1466 m1485  N/A ± N/A  N/A ± N/A HIF-1α-1468 1468 m1487 15.1± 8.8 13.4 ± 9.3 HIF-1α-1470 1470 m1489   13 ± 6.2 14.6 ± 8.6HIF-1α-1472 1472 m1491  12.9 ± 12.4  26.2 ± 23.1 HIF-1α-1474 1474 m149316.3 ± 6.6 20.4 ± 3.8 HIF-1α-1476 1476 m1495 18.3 ± 9.3  18.1 ± 10.9HIF-1α-1478 1478 m1497  9.3 ± 12.5  9.4 ± 12.6 HIF-1α-1480 1480 m1499 30.3 ± 10.7  21.8 ± 10.7 HIF-1α-1482 1482 m1501 23.9 ± 3.6   27 ± 0.8HIF-1α-1519 1519 m1538 57.9 ± 5.6  55.1 ± 11.2 HIF-1α-1552 1552 m1571  17 ± 4.7 16.6 ± 3   HIF-1α-1714 1714 m1733 36.7 ± 4   38.1 ± 3.1HIF-1α-1804 1804 m1820 25.4 ± 6.4 24.7 ± 8.1 HIF-1α-1806 1806 m1822 59.2± 1.6 53.1 ± 1.1 HIF-1α-1808 1808 m1824  46.7 ± 14.8  44.6 ± 13.4HIF-1α-1810 1810 m1826 69.6 ± 8.2 55.3 ± 5.2 HIF-1α-1936 1936 m1952 14.4± 8.2  14.9 ± 12.6 HIF-1α-1938 1938 m1954 11.6 ± 4     9 ± 2.8HIF-1α-1940 1940 m1956 17.8 ± 4.1   17 ± 4.4 HIF-1α-1942 1942 m1958 38.3± 6   42.6 ± 8.9 HIF-1α-1944 1944 m1960  30.5 ± 10.4  30.6 ± 10.3HIF-1α-1946 1946 m1962   62 ± 3.7 58.9 ± 5.4 HIF-1α-2116 2116 m2174 10.5 ± 14.9  10.6 ± 14.3 HIF-1α-2118 2118 m2176 10.4 ± 5.9  9.6 ± 5.4HIF-1α-2120 2120 m2178    8 ± 13.2 6.9 ± 18 HIF-1α-2122 2122 m2180 25.5± 6.9 27.5 ± 7.5 HIF-1α-2161 2161 m2219 12.2 ± 6.1 12.3 ± 2.8HIF-1α-2452 2452 m2504 14.3 ± 7.9  15.4 ± 13.1 HIF-1α-2584 2584 m2633  20 ± 11.3 17.6 ± 9.5 HIF-1α-2586 2586 m2635 16.2 ± 6.1  14.4 ± 11.3HIF-1α-2705 N/A m2754   16 ± 4.4 14.3 ± 6.1 HIF-1α-2796 2669 m2845 9.2 ±7    7 ± 6.8 HIF-1α-2798 2671 m2847   11 ± 8.2  5.7 ± 5.9 HIF-1α-28002673 m2849  8.3 ± 3.9  6.4 ± 4.2 HIF-1α-2802 2675 m2851  9.3 ± 11.3  7.6± 10.4 HIF-1α-2823 2696 m2872 27.4 ± 5   27.5 ± 3.1 HIF-1α-2844 2717m2893 23.3 ± 4.6 22.5 ± 4.3 HIF-1α-2846 2719 m2895 34 ± 4 29.9 ± 3  HIF-1α-2848 2721 m2897   30 ± 2.2 26.5 ± 6   HIF-1α-2850 2723 m2899 18.5± 3.8 16.7 ± 3.8 HIF-1α-2852 2725 m2901  9.7 ± 10   6 ± 6.2 HIF-1α-28542727 m2903  11.5 ± 11.1 10.5 ± 5.5 HIF-1α-2856 2729 m2905  7.4 ± 18.7 5.6 ± 21.9 HIF-1α-2858 2731 m2907  7.5 ± 5.4 5.6 ± 5  HIF-1α-2860 2733m2909  8.3 ± 2.6  6.1 ± 8.6 HIF-1α-2862 2735 m2911  9.9 ± 8.6 6.4 ± 9 HIF-1α-2864 2737 m2913 10.4 ± 8    7.1 ± 6.8 HIF-1α-2866 2739 m2915  6.9± 6.9  5.7 ± 10.9 HIF-1α-2868 2741 m2917 10.7 ± 9.2  8.9 ± 10.7HIF-1α-2870 2743 m2919  7.4 ± 4.5  6.1 ± 9.8 HIF-1α-2872 2745 m2921   11± 8.7 11.4 ± 9.1 HIF-1α-2874 2747 m2923  7.7 ± 7.4  6.4 ± 3.3HIF-1α-2876 2749 m2925  8.5 ± 12.6  7.7 ± 20.7 HIF-1α-2878 2751 m2927 11.8 ± 13.4  7.9 ± 15.7 HIF-1α-2880 2753 m2929  7.9 ± 16.5  5.5 ± 17.1HIF-1α-2882 2755 m2931  8.8 ± 2.5  5.9 ± 2.4 HIF-1α-2884 2757 m2933   8± 5.3  5.9 ± 19.9 HIF-1α-2886 2759 m2935 4.9 ± 7  3.4 ± 1.2 HIF-1α-28882761 m2937 10.4 ± 9    8.5 ± 3.4 HIF-1α-2890 2763 m2939  6.5 ± 13.6  4.8± 9.5 HIF-1α-2892 2765 m2941  24.3 ± 11.1 21.5 ± 9.4 HIF-1α-2933 2806m3042 19.3 ± 3.8   14 ± 5.1 HIF-1α-2935 2808 m3044 26.2 ± 3.6 21.9 ± 7.6HIF-1α-2963 2836 m3063 10.3 ± 4.8  7.4 ± 7.5 HIF-1α-2965 2838 m3065 17.4± 2.3 12.3 ± 2.5 HIF-1α-2986 2859 m3086 21.3 ± 4.3 17.6 ± 4.6HIF-1α-2988 2861 m3088 15.1 ± 3.8   10 ± 3.9 HIF-1α-2990 2863 m3090 15.9 ± 13.7  11.9 ± 10.8 HIF-1α-2992 2865 m3092 20.4 ± 5.4 15.2 ± 6.8HIF-1α-2994 2867 m3094 31.6 ± 4.3 25.2 ± 0.7 HIF-1α-2996 2869 m3096   31± 6.6 17.1 ± 4.5 HIF-1α-2998 2871 m3098  21.5 ± 12.8 14.6 ± 8.9HIF-1α-3000 2873 m3100 32.2 ± 9.9 24.1 ± 6.4 HIF-1α-3002 2875 m3102  N/A± N/A  N/A ± N/A HIF-1α-3004 2877 m3104  20.6 ± 10.8 17.7 ± 8.1HIF-1α-3167 3040 m3257 21.2 ± 4.5 16.1 ± 7.5 HIF-1α-3169 3042 m3259 19.7 ± 21.4 21.6 ± 9.1 HIF-1α-3171 3044 m3261   22 ± 3.6 16.4 ± 2.5HIF-1α-3173 3046 m3263  33.6 ± 10.7   26 ± 9.3 HIF-1α-3175 3048 m326555.3 ± 6.1 54.8 ± 3.3 HIF-1α-3177 3050 m3267 167.9 ± 1.1  184.3 ± 0.9 HIF-1α-3179 3052 m3269  157 ± 9.7 155.3 ± 5.1  HIF-1α-3274 3147 m336222.8 ± 9   18.2 ± 18  HIF-1α-3276 3149 m3364 18.8 ± 4.9 15.2 ± 2  HIF-1α-3278 3151 m3366 18.9 ± 9   15.9 ± 5.7 HIF-1α-3280 3153 m3368 30.6± 5.3 26.1 ± 4   HIF-1α-3358 3231 m3444 20.2 ± 10   12.1 ± 10.9HIF-1α-3360 3233 m3446 21.7 ± 9.9  14.1 ± 10.3 HIF-1α-3362 3235 m344815.3 ± 7.5 12 ± 5 HIF-1α-3364 3237 m3450  15.7 ± 17.7  12.5 ± 11.8HIF-1α-3366 3239 m3452   15 ± 11.8 14.2 ± 7   HIF-1α-3368 3241 m345417.5 ± 4   12.8 ± 3.8 HIF-1α-3426 3299 m3511 56.8 ± 2.9 51.7 ± 8.1HIF-1α-3428 3301 m3513 146.3 ± 2.8  163.7 ± 4.8  HIF-1α-3430 3303 m351588.3 ± 3.8 77.7 ± 3   HIF-1α-3448 3321 m3530  27.2 ± N/A  22.3 ± N/AHIF-1α-3450 3323 m3532  25.4 ± 24.3 12.3 ± 14  HIF-1α-3546 3419 m362014.8 ± 5.5 11.1 ± 5.4 HIF-1α-3592 3465 m3666 25.2 ± 8.2 22.5 ± 7.6HIF-1α-3594 3467 m3668   26 ± 12.8  20.4 ± 12.2 HIF-1α-3596 3469 m367026.5 ± 4.5 15.7 ± 7.2 HIF-1α-3598 3471 m3672   24 ± 5.5 17.4 ± 7.3HIF-1α-3600 3473 m3674 15.6 ± 5.8  9.9 ± 2.7 HIF-1α-3602 3475 m3676 19.4± 8.9 16.1 ± 9.9 HIF-1α-3604 3477 m3678  22.3 ± 11.6   14 ± 7.2HIF-1α-3606 3479 m3680 12.1 ± 6.6  9.3 ± 4.8 HIF-1α-3608 3481 m3682 18.9± 7.1 17.9 ± 6   HIF-1α-3608 3481 m3682   21 ± 10.8 17.7 ± 9.7HIF-1α-3610 3483 m3684 19.9 ± 3.9 17.6 ± 4.3 HIF-1α-3612 3485 m3686   21± 14.9  14.4 ± 10.9 HIF-1α-3614 3487 m3688 49.1 ± 7.2 43.1 ± 4.9HIF-1α-3616 3489 m3690 54.6 ± 7.9 47.2 ± 7.8 HIF-1α-3861 3734 m3927 15.7± 8.2 12.5 ± 4.1 HIF-1α-3863 3736 m3929 15.7 ± 1.8 10.7 ± 4.1HIF-1α-3865 3738 m3931 11.1 ± 3.8  8.6 ± 4.5 HIF-1α-3867 3740 m3933 12.8± 7.2 11.5 ± 1.9 HIF-1α-3869 3742 m3935  13.1 ± 12.4  11.2 ± 14.9HIF-1α-3871 3744 m3937  15.4 ± 15.8 10.6 ± 5.1 HIF-1α-3873 3746 m393917.4 ± 3.3 13.2 ± 2.1 HIF-1α-3875 3748 m3941 21.9 ± 2.8 17.4 ± 3  HIF-1α-3877 3750 m3943 18.6 ± 8.1 14.7 ± 9.8 HIF-1α-3916 3789 m3981 14.2± 2.8  9.3 ± 11.2 HIF-1α-3918 3791 m3983 12.3 ± 8.3 10.2 ± 6.9HIF-1α-3920 3793 m3985 26.1 ± 5.9 24.5 ± 12  HIF-1α-3922 3795 m3987   15± 15.5  13.8 ± 17.2 HIF-1α-3924 3797 m3989  14.4 ± 21.4 18.1 ± 7.1HIF-1α-3926 3799 m3991 22.8 ± 3.5 19.4 ± 2.2 HIF-1α-3928 3801 m3993 25.5± 4.5   20 ± 9.1 HIF-1α-3930 3803 m3995  13.7 ± 17.2  11.7 ± 17.3HIF-1α-4055 3928 m4119 60.3 ± 5.5 48.6 ± 3.4 HIF-1α-4057 3930 m4121 14.7± 9.3 15.2 ± 7.5 HIF-1α-4059 3932 m4123 28.6 ± 7.3 25.4 ± 6.7HIF-1α-4061 3934 m4125 30.5 ± 8.3 32 ± 8 HIF-1α-4063 3936 m4127  49.5 ±14.5  57.7 ± 10.6 HIF-1α-4065 3938 m4129 50.6 ± 4   46.2 ± 5.3HIF-1α-m38  154 ± 4.2 160.3 ± 2.5  HIF-1α-m40 114.5 ± 3.4  121.7 ± 2.6 HIF-1α-m41 96.9 ± 12  127.7 ± 7.4  HIF-1α-m42 145.7 ± 3.4  158.3 ± 3.3 HIF-1α-m43 129.5 ± 17.5 121.4 ± 9.8  HIF-1α-m44  151 ± 2.9 184.2 ± 9.7 HIF-1α-m45 116.4 ± 11.2   96 ± 17.8 HIF-1α-m46 128.7 ± 5.6  143.4 ± 3.6 HIF-1α-m47 155.1 ± 3.2  159.6 ± 2   HIF-1α-m49 137.5 ± 5.4  161.2 ± 4  HIF-1α-m50 127.5 ± 7.1  124.6 ± 7   HIF-1α-m51 147.4 ± 4   147.6 ± 9.2 HIF-1α-m52 143.5 ± 2.2  136.5 ± 2.1  HIF-1α-m53 152.8 ± 3.4  171.9 ±3.4  HIF-1α-m55 107.6 ± 4.3  125.6 ± 3.6  HIF-1α-m97  87.7 ± 10.6 89.8 ±7.1 HIF-1α-m98 86.1 ± 2.3 79.6 ± 0.9 HIF-1α-m99 130.6 ± 3.4  194.7 ±10.5 HIF-1α-m100 120.2 ± 3.1  128.5 ± 6.7  HIF-1α-m139 111.2 ± 4.5 115.7 ± 1.1  HIF-1α-m141 132.9 ± 9.2  126.4 ± 6.6  HIF-1α-m145 99.6 ±7   133.6 ± 1.4  HIF-1α-m146 101.6 ± 20.4 119.9 ± 10   HIF-1α-m148 154.3± 8.4  102.7 ± 10.4 HIF-1α-m152 97.7 ± 11    91 ± 7.2 HIF-1α-m271 98.7 ±8.8   95 ± 7.4 HIF-1α-m277  106 ± 3.9 121.6 ± 8.5  HIF-1α-m282 99.6 ±1.5 107.9 ± 11.4 HIF-1α-m283 155.4 ± 16.4 172 ± 11 HIF-1α-m284 131.2 ±8.7  129.2 ± 6.7  HIF-1α-m286 122.5 ± 4.1  125.5 ± 2.8  HIF-1α-m289   93± 6.1 91.4 ± 4.3 HIF-1α-m348 116.6 ± 7.1  100.7 ± 5.1  HIF-1α-m350   91± 10.2 86.1 ± 9.3 HIF-1α-m352  83.2 ± 15.8 92.6 ± 9.6 HIF-1α-m353 157.7± 6.8  161.8 ± 6.8  HIF-1α-m354 140.3 ± 2.7  169.5 ± 5.7  HIF-1α-m357 118 ± 2.8 123.8 ± 2.5  HIF-1α-m359 155.6 ± 3.6  149.5 ± 4.5 HIF-1α-m365  107 ± 7.8 90.9 ± 7.2 HIF-1α-m597 107.5 ± 5.6  119.5 ± 8.1 HIF-1α-m600 80.1 ± 8.2  85.7 ± 12.4 HIF-1α-m712 115.2 ± N/A 139.1 ± N/AHIF-1α-m1093  73.7 ± 13.8 84.1 ± 9.5 HIF-1α-m1593  76.7 ± 30.7  73.6 ±24.4 HIF-1α-m1595  64.9 ± 21.2  71.5 ± 18.9 HIF-1α-m1596  92.7 ± 10.7 97.6 ± 12.9 HIF-1α-m1599 104.2 ± 14.9 103.7 ± 9.9  HIF-1α-m1632 92.6 ±3   101.2 ± 2.6  HIF-1α-m1633 114 ± 12 111.3 ± 10.2 HIF-1α-m1634 111.7 ±4.6  113.8 ± 4.6  HIF-1α-m1642 89.6 ± 6.4 80.8 ± 2.5 HIF-1α-m1830 91.8 ±9.2 106.3 ± 5.2  HIF-1α-m2041   82 ± 3.6 92.3 ± 5.6 HIF-1α-m2043 57.4 ±8.2 69.2 ± 7.2 HIF-1α-m2045  68.3 ± 12.5 74.5 ± 5.4 HIF-1α-m2650   80 ±26.6  81.8 ± 21.5 HIF-1α-m3030 47.2 ± 10   42.7 ± 10.1 HIF-1α-m3557 72.3 ± 16.7  79.5 ± 15.2 HIF-1α-m3562 68.2 ± 5.6 69.9 ± 1.8HIF-1α-m3576  29.6 ± 14.3  25.9 ± 12.3 HIF-1α-m3592 55.5 ± 5.3 50.4 ±5.1 HIF-1α-m3604 85.4 ± 5.9 91.8 ± 5   HIF-1α-m4023 100.2 ± 4.6  101.9 ±4.9  HIF-1α-m4064 71.4 ± 7   69.6 ± 6.6 HIF-1α-m4065  67.5 ± 11.1  74.5± 11.6 HIF-1α-m4070 91.1 ± 6.4 70.9 ± 4.4 HIF-1α-m4549 122.5 ± 5.9 149.4 ± 25.2 HIF-1α-m4691 96.1 ± 6   90.1 ± 4.5 HIF-1α-m4692 102.4 ±5.9  108.7 ± 1.6  HIF-1α-m4693 132.2 ± 15.8 117.7 ± 13.8 HIF-1α-m470988.9 ± 6.8 96.5 ± 4.7As shown in above Table 8, 271 of 378 asymmetric DsiRNAs examined inhuman HeLa cells showed greater than 70% reduction of human HIF-1αlevels in HeLa cells at 1 nM. Of these 271 DsiRNAs, 177 exhibited 80% orgreater reduction of human HIF-1α levels in HeLa cells at 1 nM. As shownin above Table 9, a number of asymmetric DsiRNAs capable of inhibitingmouse HIF-1α levels in mouse HEPA1-6 cells at 1 nM in the environment ofa cell were also identified in such assays. Assay results of Tables 8and 9 above were also plotted and are shown in FIGS. 2A-2D. It is notedin Table 9 and corresponding FIG. 2D that assays ranging from HIF-1α-81through HIF-1α-1257 were affected by subpar transfection of Hepa1-6cells in these assays (specifically, the HPRT transfection reagent washalf as potent in these assays as in all other assays).

In certain embodiments, double stranded nucleic acids were selected thattarget the following 21 nucleotide target sequences:

TABLE 10 HIF-1α mRNA 21 Nucleotide Target Sequences of Select dsRNAsHuman HIF-1α Target Location, Transcript 21 Nucleotide SEQ Variant 1Target Sequence ID NO: HIF-1α-403 GUGAAGACAUCGCGGGGACCG 1656 HIF-1α-469AAGUUCUGAACGUCGAAAAGA 1662 HIF-1α-530 UCUGAAGUUUUUUAUGAGCUU 1668HIF-1α-691 GAUGAAUUGCUUUUAUUUGAA 1684 HIF-1α-713 GCCUUGGAUGGUUUUGUUAUG1687 HIF-1α-717 UGGAUGGUUUUGUUAUGGUUC 1689 HIF-1α-756UGAUUUACAUUUCUGAUAAUG 1690 HIF-1α-824 GUGUUUGAUUUUACUCAUCCA 1693HIF-1α-1041 ACAGUAACCAACCUCAGUGUG 1717 HIF-1α-1122 CAAAUAUUGAAAUUCCUUUAG1731 HIF-1α-1262 UAUUAUCAUGCUUUGGACUCU 1747 HIF-1α-1268CAUGCUUUGGACUCUGAUCAU 1749 HIF-1α-1271 GCUUUGGACUCUGAUCAUCUG 1750HIF-1α-1343 UACAGGAUGCUUGCCAAAAGA 1774 HIF-1α-1369 AUAUGUCUGGGUUGAAACUCA1787 HIF-1α-1379 GUUGAAACUCAAGCAACUGUC 1792 HIF-1α-1476ACUUGAUUUUCUCCCUUCAAC 1807 HIF-1α-1478 UUGAUUUUCUCCCUUCAACAA 1808HIF-1α-1482 UUUUCUCCCUUCAACAAACAG 1810 HIF-1α-1648 CACAAUCAUAUCUUUAGAUUU1814 HIF-1α-1940 GGAAGCACUAGACAAAGUUCA 1826 HIF-1α-1944GCACUAGACAAAGUUCACCUG 1828 HIF-1α-1946 ACUAGACAAAGUUCACCUGAG 1829HIF-1α-2034 UGGUAGAAAAACUUUUUGCUG 1832 HIF-1α-2730 AGCAAAAGACAAUUAUUUUAA1849 HIF-1α-2852 GGCAGCAGAAACCUACUGCAG 1859 HIF-1α-2882UUACUCAGAGCUUUGGAUCAA 1874 HIF-1α-2890 AGCUUUGGAUCAAGUUAACUG 1878HIF-1α-2925 UUCAUUCCUUUUUUUGGACAC 1884 HIF-1α-2933 UUUUUUUGGACACUGGUGGCU1885 HIF-1α-2970 CUAUUUAUAUUUUCUACAUCU 1889 HIF-1α-3055CUUAAUUUACAUUAAUGCUCU 1900 HIF-1α-3088 UCUUUAAUGCUGGAUCACAGA 1906HIF-1α-3110 AGCUCAUUUUCUCAGUUUUUU 1908 HIF-1α-3310 CCUUUUUUUUCACAUUUUACA1923 HIF-1α-3448 GAAGAAAUUUUUUUUGGCCUA 1936 HIF-1α-3450AGAAAUUUUUUUUGGCCUAUG 1937 HIF-1α-3598 UAUGUGGCAUUUAUUUGGAUA 1946HIF-1α-3616 AUAAAAUUCUCAAUUCAGAGA 1956 HIF-1α-3646 AUGUUUCUAUAGUCACUUUGC1958 HIF-1α-3670 CUCAAAAGAAAACAAUACCCU 1960 HIF-1α-3743UGUUCUGCCUACCCUGUUGGU 1961 HIF-1α-3791 CAAGAAAAAAAAAAUCAUGCA 1968HIF-1α-3861 GAUUUUAUGCACUUUGUCGCU 1970 HIF-1α-3863 UUUUAUGCACUUUGUCGCUAU1971 HIF-1α-3880 CUAUUAACAUCCUUUUUUUCA 1979 HIF-1α-3961AGUAAAUAUCUUGUUUUUUCU 1988 HIF-1α-4003 CAUUCCUUUUGCUCUUUGUGG 1993HIF-1α-4004 AUUCCUUUUGCUCUUUGUGGU 1994 HIF-1α-4005 UUCCUUUUGCUCUUUGUGGUU1995 HIF-1α-4006 UCCUUUUGCUCUUUGUGGUUG 1996 HIF-1α-4007CCUUUUGCUCUUUGUGGUUGG 1997

TABLE 11 HIF-1α mRNA 21 Nucleotide Target Sequences of AdditionalSelected dsRNAs Human HIF-1α Target Location, Transcript 21 NucleotideSEQ Variant 1 Target Sequence ID NO: HIF-1α-403 GUGAAGACAUCGCGGGGACCG1656 HIF-1α-530 UCUGAAGUUUUUUAUGAGCUU 1668 HIF-1α-691GAUGAAUUGCUUUUAUUUGAA 1684 HIF-1α-713 GCCUUGGAUGGUUUUGUUAUG 1687HIF-1α-717 UGGAUGGUUUUGUUAUGGUUC 1689 HIF-1α-1041 ACAGUAACCAACCUCAGUGUG1717 HIF-1α-1268 CAUGCUUUGGACUCUGAUCAU 1749 HIF-1α-1271GCUUUGGACUCUGAUCAUCUG 1750 HIF-1α-1343 UACAGGAUGCUUGCCAAAAGA 1774HIF-1α-1476 ACUUGAUUUUCUCCCUUCAAC 1807 HIF-1α-1648 CACAAUCAUAUCUUUAGAUUU1814 HIF-1α-1944 GCACUAGACAAAGUUCACCUG 1828 HIF-1α-2034UGGUAGAAAAACUUUUUGCUG 1832 HIF-1α-2730 AGCAAAAGACAAUUAUUUUAA 1849HIF-1α-2925 UUCAUUCCUUUUUUUGGACAC 1884 HIF-1α-2963 AAGCAGUCUAUUUAUAUUUUC1887 HIF-1α-2963 AAGCAGUCUAUUUAUAUUUUC 1887 HIF-1α-2965GCAGUCUAUUUAUAUUUUCUA 1888 HIF-1α-3055 CUUAAUUUACAUUAAUGCUCU 1900HIF-1α-3110 AGCUCAUUUUCUCAGUUUUUU 1908 HIF-1α-3310 CCUUUUUUUUCACAUUUUACA1923 HIF-1α-3310 CCUUUUUUUUCACAUUUUACA 1923 HIF-1α-3374CACAAUAUAUUUUCUUAAAAA 1930 HIF-1α-3448 GAAGAAAUUUUUUUUGGCCUA 1936HIF-1α-3450 AGAAAUUUUUUUUGGCCUAUG 1937 HIF-1α-3616 AUAAAAUUCUCAAUUCAGAGA1956 HIF-1α-3670 CUCAAAAGAAAACAAUACCCU 1960 HIF-1α-3743UGUUCUGCCUACCCUGUUGGU 1961 HIF-1α-3791 CAAGAAAAAAAAAAUCAUGCA 1968HIF-1α-3880 CUAUUAACAUCCUUUUUUUCA 1979 HIF-1α-3920 GUAAUUUUAGAAGCAUUAUUU1982 HIF-1α-3922 AAUUUUAGAAGCAUUAUUUUA 1983 HIF-1α-4003CAUUCCUUUUGCUCUUUGUGG 1993 HIF-1α-4004 AUUCCUUUUGCUCUUUGUGGU 1994HIF-1α-4005 UUCCUUUUGCUCUUUGUGGUU 1995 HIF-1α-4006 UCCUUUUGCUCUUUGUGGUUG1996 HIF-1α-4007 CCUUUUGCUCUUUGUGGUUGG 1997 HIF-1α-4008CUUUUGCUCUUUGUGGUUGGA 1998 HIF-1α-4009 UUUUGCUCUUUGUGGUUGGAU 1999HIF-1α-4010 UUUGCUCUUUGUGGUUGGAUC 2000 HIF-1α-4012 UGCUCUUUGUGGUUGGAUCUA2001

TABLE 12 HIF-1α mRNA 21 Nucleotide Target Sequences of Further SelecteddsRNAs Human HIF-1α Target Location, Transcript 21 Nucleotide SEQVariant 1 Target Sequence ID NO: HIF-1α-403 GUGAAGACAUCGCGGGGACCG 1656HIF-1α-3448 GAAGAAAUUUUUUUUGGCCUA 1936 HIF-1α-3791 CAAGAAAAAAAAAAUCAUGCA1968 HIF-1α-3880 CUAUUAACAUCCUUUUUUUCA 1979 HIF-1α-4003CAUUCCUUUUGCUCUUUGUGG 1993 HIF-1α-4004 AUUCCUUUUGCUCUUUGUGGU 1994HIF-1α-4005 UUCCUUUUGCUCUUUGUGGUU 1995 HIF-1α-4006 UCCUUUUGCUCUUUGUGGUUG1996 HIF-1α-4007 CCUUUUGCUCUUUGUGGUUGG 1997

Example 3: DsiRNA Inhibition of HIF-1α—Secondary Screen

96 asymmetric DsiRNAs of the above experiment were then examined in asecondary assay (“Phase 2”), with results of such assays presented inhistogram form in FIGS. 3A-3F. Specifically, the 96 asymmetric DsiRNAsselected from the 450 tested above were assessed for inhibition of humanHIF-1α at 1 nM, 0.3 nM and 0.1 nM in the environment of human HeLa cells(FIGS. 3A-3C). These 96 asymmetric DsiRNAs were also assessed forinhibition of mouse HIF-1α at 1 nM, 0.3 nM and 0.1 nM in the environmentof mouse HEPA1-6 cells (FIGS. 3D-3F). As shown in FIGS. 3A-3C, aremarkable number of asymmetric DsiRNAs reproducibly exhibited robusthuman HIF-1α inhibitory efficacies at sub-nanomolar concentrations whenassayed in the environment of HeLa cells. In addition, as shown in FIGS.3D-3F, a number of these asymmetric DsiRNAs also showed robust mouseHIF-1α inhibitory efficacies at 1 nM, 300 pM and 100 pM when assayed inthe environment of mouse HEPA1-6 cells. (Meanwhile, both humanHIF-1α-specific and mouse HIF-1α-specific inhibitory asymmetric DsiRNAswere also identified.)

Example 4: Inhibition of HIF-1α by Additional Preferred DsiRNAs

Remaining DsiRNA molecules shown in Tables 3 and 6-7 above possessingsense and antisense strand sequences as shown and targeting HIF-1αwild-type sequences (and variant sequences where applicable) aredesigned and synthesized as described above and tested in HeLa cells(and, optionally, in mouse HEPA1-6 cells) for inhibitory efficacy asdescribed in Examples 2 and 3 above. The ability of these DsiRNA agentsto inhibit HIF-1α expression is optionally assessed in comparison tocorresponding HIF-1α target sequence-directed 21mer siRNAs (21nucleotide target sequences of HIF-1α dsRNA agents described herein arepresented in Table 5 above). A significant number of the remainingselected DsiRNA agents of Tables 3 and 6-7 above are predicted to showefficacy as HIF-1α inhibitors, and are tested at 1 nM, 300 pM and at 100pM concentrations in the environment of a cell. These additional DsiRNAsand the DsiRNAs tested herein are also examined for the ability tooutperform cognate siRNAs, as determined via measurement of efficacy indecreasing levels of HIF-1α target relative to a cognate 21mer siRNAagent. The duration of such inhibitory effects is also examined at both24 hours and 48 hours post-administration, with concentrations of 0.1nM, 0.3 nM, 1 nM and 5 nM tested. DsiRNAs of the instant invention arethereby examined for the ability to outperform their cognate 21mersiRNA, as determined via measurement of potency and/or duration ofeffect.

Example 5: Modified Forms of HIF-1α-Targeting DsiRNAs Reduced HIF-1αLevels In Vitro

24 HIF-1α-targeting DsiRNAs (HIF-1α-921, HIF-1α-1122, HIF-1α-1381,HIF-1α-1385, HIF-1α-1478, HIF-1α-2798, HIF-1α-2802, HIF-1α-2852,HIF-1α-2856, HIF-1α-2858, HIF-1α-2862, HIF-1α-2874, HIF-1α-2876,HIF-1α-2880, HIF-1α-2882, HIF-1α-2890, HIF-1α-2963, HIF-1α-2988,HIF-1α-3310, HIF-1α-3865, HIF-1α-3916, HIF-1α-3930, HIF-1α-4012 andHIF-1α-m3576) were prepared with 2′-O-methyl modification patterns asshown in schematics of FIGS. 4A to 4X. For each of the 24 DsiRNAsequences, DsiRNAs possessing each of the four modification patternswere assayed for HIF-1α inhibition in human HeLa cells at 0.1 nM (inparallel assays) and 1.0 nM concentrations in the environment of theHeLa cells. Results of these experiments are presented as histograms inFIGS. 4A to 4X. In general, the 24 DsiRNA sequences exhibited a trendtowards reduced efficacy of HIF-1α inhibition as the extent of2′-O-methyl modification of the guide strand increased. However, foralmost all DsiRNA sequences examined a modification pattern could beidentified that allowed the DsiRNA to retain significant HIF-1αinhibitory efficacy in vitro. It was also notable that many DsiRNAs(e.g., HIF-1α-921, HIF-1α-1122, HIF-1α-1385, HIF-1α-2856, HIF-1α-2882,HIF-1α-2890, HIF-1α-2963, HIF-1α-3865, HIF-1α-3916 and HIF-1α-4012)exhibited robust HIF-1α inhibitory efficacy in even the most highlymodified states examined. These data indicated that modificationstrategies designed to stabilize such DsiRNAs and/or reduceimmunogenicity of such DsiRNAs when therapeutically administered to asubject in vivo could be implemented while retaining knockdown activity.

Example 6: HIF-1α-Targeting DsiRNAs Reduced HIF-1α Protein Levels InVitro

The impact of a HIF-1α-targeting DsiRNA upon cellular protein levels wasexamined in vitro. Specifically, as shown in FIG. 5, delivery ofHIF-1α-targeting DsiRNA, HIF-1α-1385 (here, possessing the 2′-O-methylmodification pattern referred to above as “M4”) to human HeLa cellsdramatically reduced HIF-1α protein levels. In such experiments, DsiRNAtransfection of HeLa cells occurred on day 0 at 10 nM concentration,with desferrioxamine (DFO) added to indicated HeLa cells at 200 μMconcentration on day 1 for purpose of inducing HIF-1α expression (asshown in the left-hand lanes of FIG. 5, such DFO treatment was necessaryfor detection of HIF-1α knockdown in the assayed cells). On day 2, HeLacells were harvested and nuclear proteins were isolated for Western blotanalysis (via use of a NE-PER™ Nuclear and Cytoplasmic ExtractionReagents kit from Thermo-Fisher Scientific™, Cat # PI78833)). TheWestern blot of FIG. 5 was probed with anti-HIF-1α antibody (top panel),with Lamin A/C protein levels (bottom panel, resulting from probing theWestern blot with anti-Lamin A/C antibody) assayed for purpose ofnormalization of HIF-1α protein levels between samples. In FIG. 5, the“Control DsiRNA 114” was a non-specific, scrambled control DsiRNA.Notably, and as expected, the HIF-1α mRNA knockdown demonstrated for theHIF-1α-1385-M4 DsiRNA in FIG. 4D was shown to correlate directly withthe significant knockdown of HIF-1α protein levels that was observed forthe HIF-1α-1385-M4 DsiRNA in FIG. 5.

Example 7: Dose-Response of Seven Selected HIF-1α-Targeting DsiRNAs

Seven different HIF-1α-targeting DsiRNAs (HIF-1α-2882, HIF-1α-3865,HIF-1α-2856, HIF-1α-2874, HIF-1α-3916, HIF-1α-4012 and HIF-1α-1385) wereselected for assessment of dose-response characteristics in vitro inHeLa cells. Individual modified forms of HIF-1α-2882 (−M8), HIF-1α-3865(−M8), HIF-1α-2856 (−M8), HIF-1α-2874 (−M3), HIF-1α-3916 (−M1) andHIF-1α-4012 (−M1) were assessed, while two distinct modified forms ofHIF-1α-1385, HIF-1α-1385-M1 and HIF-1α-1385-M4, were assayed. As shownin FIG. 6, sub-nanomolar IC₅₀ values were observed for each DsiRNA, withspecific values ranging from 1.41 pM (HIF-1α-4012-M1) to 42.1 pM(HIF-1α-1385-M4). Thus, HIF-1α-targeting DsiRNAs were furtherdemonstrated to be remarkably potent and effective inhibitors of HIF-1αexpression.

Example 8: Further DsiRNA Inhibition of HIF-1α

Forty DsiRNA molecules selected from Table 2 above that target HIF-1αwild-type sequences were designed and synthesized as described above andtested in HeLa cells for inhibitory efficacy as described in Example 1above. The ability of these DsiRNA agents to inhibit HIF-1α expressionwas assessed in comparison to corresponding HIF-1α targetsequence-directed 21mer siRNAs (tested anti-HIF-1α 21mer agents weredesigned with antisense strands complementary to the 21 nucleotidetarget sequences as shown in Table 5 above corresponding to testedDsiRNA agents; FIG. 1 also presents a comparison of structures used inthe experiment). All DsiRNA agents showed efficacy as HIF-1α inhibitors,with 35 of 40 tested DsiRNA agents exhibiting greater than 50% reductionof the HIF-1α target. As shown in FIG. 7, for twenty-four of fortyDsiRNA-cognate siRNA pairs tested, the DsiRNA agent exhibitedsignificantly superior efficacy in decreasing levels of HIF-1α targetthan the cognate siRNA agent. Such inhibitory effects were examined at24 hours post-administration, at concentrations of 0.1 nM. This resultwas in marked contrast to the only four of 40 instances in which thecognate siRNA agent outperformed the DsiRNA agent (FIG. 7). Thus,statistically significant distinctions were observed between DsiRNAs andmatched cognate siRNAs (possessing aligned projected Ago2 cleavagesites) across the HIF-1α target RNA. By a large majority, the DsiRNAsdramatically and unexpectedly outperformed cognate siRNAs. Importantly,these results demonstrated that DsiRNA activity did not directlycorrelate with siRNA activity, nor did the converse hold. Accordingly,the above results demonstrated that DsiRNAs and siRNAs engage the RNAinterference machinery differently, and that DsiRNAs and siRNAs—in spiteof both comprising double-stranded RNA—are, in fact, different drugs.

Example 9: Additional Modified Forms of HIF-1α-Targeting DsiRNAs ReducedHIF-1α Levels In Vitro

24 HIF-1α-targeting DsiRNAs (HIF-1α-403, HIF-1α-691, HIF-1α-717,HIF-1α-1041, HIF-1α-1271, HIF-1α-1343, HIF-1α-1385, HIF-1α-1476,HIF-1α-1648, HIF-1α-2034, HIF-1α-2730, HIF-1α-2856, HIF-1α-2925,HIF-1α-2963, HIF-1α-3110, HIF-1α-3310, HIF-1α-3448, HIF-1α-3616,HIF-1α-3670, HIF-1α-3791, HIF-1α-3880, HIF-1α-3922, HIF-1α-4005 andHIF-1α-4012) were prepared with 2′-O-methyl modification patterns onguide and passenger strands as indicated within x-axis identifiers ofFIGS. 8A to 8H (e.g., an identifier of “M14-M12 HIF-1α-691” in FIG. 8Aindicates that the guide strand of the modified HIF-1α-691duplexpossesses the “M14” modification pattern while the passenger strandpossesses the “M12” modification pattern). For each of the 24 DsiRNAsequences, four different combinations of guide and passenger strandmodifications were tested, via assay for human HIF-1α inhibition inhuman HeLa cells at 0.1 nM (in parallel assays) and 1.0 nMconcentrations in the environment of the HeLa cells, as well as assayfor mouse HIF-1α inhibition in mouse Hepa 1-6 cells at 0.1 nM (inparallel assays) and 1.0 nM concentrations in the environment of theHepa 1-6 cells. Results of these experiments are presented as histogramsin FIGS. 8A to 8H. In general, as for modifications of only the guidestrands in Example 5 above, the 24 DsiRNA sequences exhibited a trendtowards reduced efficacy of HIF-1α inhibition as the extent of2′-O-methyl modification of guide and passenger strands increased.However, for almost all DsiRNA sequences examined, a modificationpattern could be identified that allowed the DsiRNA to retainsignificant HIF-1α inhibitory efficacy in vitro. It was also notablethat many DsiRNAs (e.g., HIF-1α-691, HIF-1α-1476, HIF-1α-3670,HIF-1α-3791 and HIF-1α-4012) exhibited robust HIF-1α inhibitory efficacyin even the most highly modified states examined. These data furtherindicated that modification strategies of both guide and passengerstrand to stabilize such DsiRNAs and/or reduce immunogenicity of suchDsiRNAs when therapeutically administered to a subject in vivo could beimplemented while retaining knockdown activity.

Example 10: In Vivo Efficacy of HIF-1α-Targeting DsiRNAs in TargetedTissues

Eight DsiRNAs directed against HIF-1α and possessing guide strand2′-O-methyl modification patterns (HIF-1α-1385-M4, HIF-1α-1478-M3,HIF-1α-2856-M4, HIF-1α-2882-M8, HIF-1α-2963-M4, HIF-1α-3865-M3,HIF-1α-3916-M3 and HIF-1α-4012-M1, with guide strand modificationpatterns indicated) were examined for the ability to inhibit HIF-1α mRNAlevels in vivo. To perform such assessment, DsiRNAs were formulated inInVivoFectamine™ 2.0 (InVitrogen™), and were administered at a dose of10 mg/kg body weight. Ten groups of CD1 female mice were injected oncewith one of the eight different HIF-1α-targeting DsiRNAs (n=5/group).Liver tissues were then collected at 72 hours post-injection. A Promega™SV96 RNA isolation kit was used to extract RNA from harvested livertissues. A Transcriptor First Strand cDNA Synthesis Kit (Roche™ #04 897030 001) was then used for cDNA synthesis, which involved input of 3 ulof total RNA, Oligo(dT) as primer and a pre-heat of about five minutesat 70° C. before adding cDNA mix. A 1/20 dilution of cDNA was thenprepared and 4 ul of this dilution was used for qPCR using iQ MultiplexPowermix kit (BioRad™ #172-5849). Mm-HIF1α-FAM and Mm-HPRT-Cy5primers/probes were used respectively as target and housekeeping geneprimers for performance of qPCR in multiplex reactions. As shown in FIG.9, each of the HIF-1α-targeting DsiRNAs examined was shown to reducemouse HIF-1α levels in normal mouse liver by approximately 80% or moreat three days post-injection. Thus, HIF-1α-targeting DsiRNAs exhibitedexceptional in vivo activities.

Example 11: Indications

The present body of knowledge in HIF-1α research indicates the need formethods to assay HIF-1α activity and for compounds that can regulateHIF-1α expression for research, diagnostic, and therapeutic use. Asdescribed herein, the nucleic acid molecules of the present inventioncan be used in assays to diagnose disease state related to HIF-1αlevels. In addition, the nucleic acid molecules can be used to treatdisease state related to HIF-1α misregulation, levels, etc.

Particular disorders and disease states that can be associated withHIF-1α expression modulation include, but are not limited to cancerand/or proliferative diseases, conditions, or disorders and otherdiseases, conditions or disorders that are related to or will respond tothe levels of HIF-1α in a cell or tissue, alone or in combination withother therapies. Particular degenerative and disease states that areassociated with HIF-1α expression modulation include but are not limitedto, for example, renal cancer, breast cancer, lung cancer, ovariancancer, cervical cancer, esophageal cancer, oropharyngeal cancer, andpancreatic cancer.

Gemcitabine and cyclophosphamide are non-limiting examples ofchemotherapeutic agents that can be combined with or used in conjunctionwith the nucleic acid molecules (e.g. DsiRNA molecules) of the instantinvention. Those skilled in the art will recognize that other drugs suchas anti-cancer compounds and therapies can be similarly be readilycombined with the nucleic acid molecules of the instant invention (e.g.DsiRNA molecules) and are hence within the scope of the instantinvention. Such compounds and therapies are well known in the art (seefor example Cancer: Principles and Practice of Oncology, Volumes 1 and2, eds Devita, V. T., Hellman, S., and Rosenberg, S. A., J.B. LippincottCompany, Philadelphia, USA) and include, without limitations,antifolates; fluoropyrimidines; cytarabine; purine analogs; adenosineanalogs; amsacrine; topoisomerase I inhibitors; anthrapyrazoles;retinoids; antibiotics such as bleomycin, anthacyclins, mitomycin C,dactinomycin, and mithramycin; hexamethylmelamine; dacarbazine;1-asperginase; platinum analogs; alkylating agents such as nitrogenmustard, melphalan, chlorambucil, busulfan, ifosfamide,4-hydroperoxycyclophosphamide, nitrosoureas, thiotepa; plant derivedcompounds such as vinca alkaloids, epipodophyllotoxins, taxol;Tamoxifen; radiation therapy; surgery; nutritional supplements; genetherapy; radiotherapy such as 3D-CRT; immunotoxin therapy such as ricin,monoclonal antibodies Herceptin; and the like. For combination therapy,the nucleic acids of the invention are prepared in one of two ways.First, the agents are physically combined in a preparation of nucleicacid and chemotherapeutic agent, such as a mixture of a nucleic acid ofthe invention encapsulated in liposomes and ifosfamide in a solution forintravenous administration, wherein both agents are present in atherapeutically effective concentration (e.g., ifosfamide in solution todeliver 1000-1250 mg/m2/day and liposome-associated nucleic acid of theinvention in the same solution to deliver 0.1-100 mg/kg/day).Alternatively, the agents are administered separately but simultaneouslyin their respective effective doses (e.g., 1000-1250 mg/m2/d ifosfamideand 0.1 to 100 mg/kg/day nucleic acid of the invention).

Those skilled in the art will recognize that other compounds andtherapies used to treat the diseases and conditions described herein cansimilarly be combined with the nucleic acid molecules of the instantinvention (e.g. siNA molecules) and are hence within the scope of theinstant invention.

Example 12: Serum Stability for DsiRNAs

Serum stability of DsiRNA agents is assessed via incubation of DsiRNAagents in 50% fetal bovine serum for various periods of time (up to 24h) at 37° C. Serum is extracted and the nucleic acids are separated on a20% non-denaturing PAGE and can be visualized with Gelstar stain.Relative levels of protection from nuclease degradation are assessed forDsiRNAs (optionally with and without modifications).

Example 13: Use of Additional Cell Culture Models to Evaluate theDown-Regulation of HIF-1α Gene Expression

A variety of endpoints have been used in cell culture models to look atHIF-1α-mediated effects after treatment with anti-HIF-1α agents.Phenotypic endpoints include inhibition of cell proliferation, RNAexpression, and reduction of HIF-1α protein expression. Because HIF-1αmutations are directly associated with increased proliferation ofcertain tumor cells, a proliferation endpoint for cell culture assays iscan be used as a screen. There are several methods by which thisendpoint can be measured. Following treatment of cells with DsiRNA,cells are allowed to grow (typically 5 days), after which the cellviability, the incorporation of bromodeoxyuridine (BrdU) into cellularDNA and/or the cell density are measured. The assay of cell density canbe done in a 96-well format using commercially available fluorescentnucleic acid stains (such as Syto® 13 or CyQuant®). As a secondary,confirmatory endpoint, a DsiRNA-mediated decrease in the level of HIF-1αprotein expression can be evaluated using a HIF-1α-specific ELISA.

Example 14: Evaluation of Anti-HIF-1α DsiRNA Efficacy in a Mouse Modelof HIF-1α Misregulation

Anti-HIF-1α DsiRNA chosen from in vitro assays can be further tested inmouse models, including, e.g., xenograft and other animal models asrecited above. In one example, mice possessing misregulated (e.g.,elevated) HIF-1α levels are administered a DsiRNA agent of the presentinvention via hydrodynamic tail vein injection. 3-4 mice per group(divided based upon specific DsiRNA agent tested) are injected with 50μg or 200 μg of DsiRNA. Levels of HIF-1α RNA are evaluated usingRT-qPCR. Additionally or alternatively, levels of HIF-1α (e.g., HIF-1αprotein levels and/or cancer cell/tumor formation, growth or spread) canbe evaluated using an art-recognized method, or phenotypes associatedwith misregulation of HIF-1α (e.g., tumor formation, growth, metastasis,etc.) are monitored (optionally as a proxy for measurement of HIF-1αtranscript or HIF-1α protein levels). Active DsiRNA in such animalmodels can also be subsequently tested in combination with standardchemotherapies.

Example 15: Diagnostic Uses

The DsiRNA molecules of the invention can be used in a variety ofdiagnostic applications, such as in the identification of moleculartargets (e.g., RNA) in a variety of applications, for example, inclinical, industrial, environmental, agricultural and/or researchsettings. Such diagnostic use of DsiRNA molecules involves utilizingreconstituted RNAi systems, for example, using cellular lysates orpartially purified cellular lysates. DsiRNA molecules of this inventioncan be used as diagnostic tools to examine genetic drift and mutationswithin diseased cells. The close relationship between DsiRNA activityand the structure of the target HIF-1α RNA allows the detection ofmutations in a region of the HIF-1α molecule, which alters thebase-pairing and three-dimensional structure of the target HIF-1αRNA. Byusing multiple DsiRNA molecules described in this invention, one can mapnucleotide changes, which are important to RNA structure and function invitro, as well as in cells and tissues. Cleavage of target HIF-1α RNAswith DsiRNA molecules can be used to inhibit gene expression and definethe role of specified gene products in the progression of aHIF-1α-associated disease or disorder. In this manner, other genetictargets can be defined as important mediators of the disease. Theseexperiments will lead to better treatment of the disease progression byaffording the possibility of combination therapies (e.g., multipleDsiRNA molecules targeted to different genes, DsiRNA molecules coupledwith known small molecule inhibitors, or intermittent treatment withcombinations of DsiRNA molecules and/or other chemical or biologicalmolecules). Other in vitro uses of DsiRNA molecules of this inventionare well known in the art, and include detection of the presence of RNAsassociated with a disease or related condition. Such RNA is detected bydetermining the presence of a cleavage product after treatment with aDsiRNA using standard methodologies, for example, fluorescence resonanceemission transfer (FRET).

In a specific example, DsiRNA molecules that cleave only wild-type ormutant or polymorphic forms of the target HIF-1α RNA are used for theassay. The first DsiRNA molecules (i.e., those that cleave onlywild-type forms of target HIF-1α RNA) are used to identify wild-typeHIF-1α RNA present in the sample and the second DsiRNA molecules (i.e.,those that cleave only mutant or polymorphic forms of target RNA) areused to identify mutant or polymorphic HIF-1α RNA in the sample. Asreaction controls, synthetic substrates of both wild-type and mutant orpolymorphic HIF-1α RNA are cleaved by both DsiRNA molecules todemonstrate the relative DsiRNA efficiencies in the reactions and theabsence of cleavage of the “non-targeted” HIF-1α RNA species. Thecleavage products from the synthetic substrates also serve to generatesize markers for the analysis of wild-type and mutant HIF-1α RNAs in thesample population. Thus, each analysis requires two DsiRNA molecules,two substrates and one unknown sample, which is combined into sixreactions. The presence of cleavage products is determined using anRNase protection assay so that full-length and cleavage fragments ofeach HIF-1α RNA can be analyzed in one lane of a polyacrylamide gel. Itis not absolutely required to quantify the results to gain insight intothe expression of mutant or polymorphic HIF-1α RNAs and putative risk ofHIF-1α-associated phenotypic changes in target cells. The expression ofHIF-1α mRNA whose protein product is implicated in the development ofthe phenotype (i.e., disease related/associated) is adequate toestablish risk. If probes of comparable specific activity are used forboth transcripts, then a qualitative comparison of HIF-1α RNA levels isadequate and decreases the cost of the initial diagnosis. Higher mutantor polymorphic form to wild-type ratios are correlated with higher riskwhether HIF-1α RNA levels are compared qualitatively or quantitatively.

All patents and publications mentioned in the specification areindicative of the levels of skill of those skilled in the art to whichthe invention pertains. All references cited in this disclosure areincorporated by reference to the same extent as if each reference hadbeen incorporated by reference in its entirety individually.

One skilled in the art would readily appreciate that the presentinvention is well adapted to carry out the objects and obtain the endsand advantages mentioned, as well as those inherent therein. The methodsand compositions described herein as presently representative ofpreferred embodiments are exemplary and are not intended as limitationson the scope of the invention. Changes therein and other uses will occurto those skilled in the art, which are encompassed within the spirit ofthe invention, are defined by the scope of the claims.

It will be readily apparent to one skilled in the art that varyingsubstitutions and modifications can be made to the invention disclosedherein without departing from the scope and spirit of the invention.Thus, such additional embodiments are within the scope of the presentinvention and the following claims. The present invention teaches oneskilled in the art to test various combinations and/or substitutions ofchemical modifications described herein toward generating nucleic acidconstructs with improved activity for mediating RNAi activity. Suchimproved activity can comprise improved stability, improvedbioavailability, and/or improved activation of cellular responsesmediating RNAi. Therefore, the specific embodiments described herein arenot limiting and one skilled in the art can readily appreciate thatspecific combinations of the modifications described herein can betested without undue experimentation toward identifying DsiRNA moleculeswith improved RNAi activity.

The invention illustratively described herein suitably can be practicedin the absence of any element or elements, limitation or limitationsthat are not specifically disclosed herein. Thus, for example, in eachinstance herein any of the terms “comprising”, “consisting essentiallyof”, and “consisting of” may be replaced with either of the other twoterms. The terms and expressions which have been employed are used asterms of description and not of limitation, and there is no intentionthat in the use of such terms and expressions of excluding anyequivalents of the features shown and described or portions thereof, butit is recognized that various modifications are possible within thescope of the invention claimed. Thus, it should be understood thatalthough the present invention has been specifically disclosed bypreferred embodiments, optional features, modification and variation ofthe concepts herein disclosed may be resorted to by those skilled in theart, and that such modifications and variations are considered to bewithin the scope of this invention as defined by the description and theappended claims.

In addition, where features or aspects of the invention are described interms of Markush groups or other grouping of alternatives, those skilledin the art will recognize that the invention is also thereby describedin terms of any individual member or subgroup of members of the Markushgroup or other group.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. The terms “comprising,” “having,” “including,” and “containing”are to be construed as open-ended terms (i.e., meaning “including, butnot limited to,”) unless otherwise noted. Recitation of ranges of valuesherein are merely intended to serve as a shorthand method of referringindividually to each separate value falling within the range, unlessotherwise indicated herein, and each separate value is incorporated intothe specification as if it were individually recited herein. All methodsdescribed herein can be performed in any suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof any and all examples, or exemplary language (e.g., “such as”)provided herein, is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention unlessotherwise claimed. No language in the specification should be construedas indicating any non-claimed element as essential to the practice ofthe invention.

Embodiments of this invention are described herein, including the bestmode known to the inventors for carrying out the invention. Variationsof those embodiments may become apparent to those of ordinary skill inthe art upon reading the foregoing description.

The inventors expect skilled artisans to employ such variations asappropriate, and the inventors intend for the invention to be practicedotherwise than as specifically described herein. Accordingly, thisinvention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

We claim:
 1. A double stranded nucleic acid (dsNA) comprising first andsecond nucleic acid strands comprising RNA, wherein said first nucleicacid strand is 15-50 nucleotides in length and said second nucleic acidstrand of said dsNA is sufficiently complementary to SEQ ID NO: 1128along at least 20 nucleotides of said second nucleic acid strand lengthto reduce HIF-1α target mRNA expression when said double strandednucleic acid is introduced into a mammalian cell.
 2. A dsNA moleculeselected from the group consisting of: a dsNA molecule comprising firstand second nucleic acid strands comprising RNA, wherein said firstnucleic acid strand is 15-50 nucleotides in length and said secondnucleic acid strand of said dsNA is 20-50 nucleotides in length andwherein said second nucleic acid strand is sufficiently complementary toSEQ ID NO: 1128 along at least 20 nucleotides of said second nucleicacid strand length to reduce HIF-1α target mRNA expression when saiddouble stranded nucleic acid is introduced into a mammalian cell; a dsNAconsisting of a sense region and an antisense region, wherein said senseregion and said antisense region together form a duplex regionconsisting of 25-35 base pairs and said antisense region comprises asequence that is the complement of SEQ ID NO: 1128 along at least 20nucleotides of said antisense region; and from zero to two 3′ overhangregions, wherein each overhang region is six or fewer nucleotides inlength, wherein the dsNA reduces HIF-1α target mRNA expression when thedsNA is introduced into a mammalian cell; a dsNA comprising first andsecond nucleic acid strands and a duplex region of at least 25 basepairs, wherein said first nucleic strand is 25-34 nucleotides in lengthand said second nucleic acid strand of said dsNA is 26-50 nucleotides inlength and comprises 1-5 single-stranded nucleotides at its 3′ terminusand wherein (a) said second nucleic acid strand is sufficientlycomplementary to SEQ ID NO:1128 along at least 20 nucleotides of saidsecond nucleic acid strand length to reduce HIF-1α target geneexpression when said double stranded nucleic acid is introduced into amammalian cell; or (b) the 3′ terminus of said first nucleic acid strandand the 5′ terminus of said second nucleic acid strand form a blunt end,and said second nucleic acid strand is sufficiently complementary to SEQID NO: 1128 along at least 20 nucleotides of said second nucleic acidstrand length to reduce HIF-1α mRNA expression when said double strandednucleic acid is introduced into a mammalian cell; and a dsNA thatinhibits the expression of HIF-1α, wherein the dsNA comprises a firstnucleic acid strand comprising SEQ ID NO: 750 and a second nucleic acidstrand comprising SEQ ID NO:
 372. 3. The dsNA of claim 1 comprising aduplex region of length selected from the group consisting of at least25 base pairs, 19-21 base pairs, and 21-25 base pairs.
 4. The dsNA ofclaim 1, wherein said second nucleic acid strand comprises 1-5single-stranded nucleotides at its 3′ terminus.
 5. The dsNA of claim 1,wherein said first nucleic acid strand and/or said second nucleic acidstrand is 25-50 nucleotides in length.
 6. The dsNA of claim 1, whereinstarting from the first nucleotide (position 1) at the 3′ terminus ofthe first nucleic acid strand, position 1, 2 and/or 3 is substitutedwith a modified nucleotide.
 7. The dsNA of claim 1, wherein said 3′terminus of said first nucleic acid strand and said 5′ terminus of saidsecond nucleic acid strand form a blunt end.
 8. The dsNA of claim 1,wherein said first nucleic acid strand is 25 nucleotides in length andsaid second nucleic acid strand is 27 nucleotides in length.
 9. The dsNAof claim 1 selected from the group consisting of: a dsNA wherein saidfirst nucleic acid strand comprises SEQ ID NO: 750; a dsNA wherein saidsecond nucleic acid strand comprises SEQ ID NO: 372; and a dsNA whereinsaid first nucleic acid strand comprises SEQ ID NO: 750 and wherein saidsecond nucleic acid strand comprises SEQ ID NO:
 372. 10. The dsNA ofclaim 1, wherein said second nucleic acid strand comprises amodification pattern selected from the group consisting of AS-MI toAS-M40 and AS-M1* to AS-M40*, and/or wherein said first oligonucleotidestrand comprises a modification pattern selected from the groupconsisting of SM1 to SM16.
 11. The dsNA of claim 1, wherein said dsNA iscleaved endogenously in said cell by Dicer.
 12. A method for reducingexpression of a target HIF-1α gene in a mammalian cell comprisingcontacting a mammalian cell in vitro with the dsNA of claim 1 in anamount sufficient to reduce expression of a target HIF-1α mRNA in saidcell.
 13. A method for reducing expression of a target HIF-1α mRNA in amammal comprising administering the dsNA of claim 1 to a mammal in anamount sufficient to reduce expression of a target HIF-1α mRNA in themammal.
 14. A method for selectively inhibiting the growth of a cellcomprising contacting a cell with an amount of the dsNA of claim 1sufficient to inhibit the growth of the cell.
 15. A formulationcomprising the dsNA of claim 1, wherein said dsNA is present in anamount effective to reduce target HIF-1α mRNA levels when said dsNA isintroduced into a mammalian cell in vitro by an amount (expressed by %)selected from the group consisting of at least 10%, at least 50% and atleast 80-90%.
 16. An isolated mammalian cell containing the dsNA ofclaim
 1. 17. A pharmaceutical composition comprising the dsNA of claim 1and a pharmaceutically acceptable carrier.
 18. A kit comprising the dsNAof claim 1 and packaging materials therefore.
 19. A method for treatingor preventing a HIF-1α-associated disease or disorder in a subjectcomprising administering the dsNA of claim 1 and a pharmaceuticallyacceptable carrier to the subject in an amount sufficient to treat orprevent said HIF-1α-associated disease or disorder in said subject,thereby treating or preventing said HIF-1α-associated disease ordisorder in said subject.
 20. A composition possessing HIF-1α inhibitoryactivity consisting essentially of the double stranded nucleic acid(dsNA) of claim
 1. 21. The dsNA of claim 2, wherein said first nucleicacid strand is 15-50 nucleotides in length and said second nucleic acidstrand of said dsNA is 20-50 nucleotides in length and wherein saidsecond nucleic acid strand is complementary to SEQ ID NO: 1128 along atleast 20 contiguous nucleotides of said second nucleic acid strandlength and said double stranded nucleic acid reduces HIF-1α target mRNAexpression when said double stranded nucleic acid is introduced into amammalian cell.
 22. The dsNA of claim 2, wherein said sense region andsaid antisense region together form a duplex region consisting of 25-35base pairs and said antisense region comprises a sequence that is thecomplement of SEQ ID NO: 1128 along at least 20 nucleotides of saidantisense region; and from zero to two 3′ overhang regions, wherein eachoverhang region is six or fewer nucleotides in length.
 23. The dsNA ofclaim 2, wherein the first and second nucleic acid strands form a duplexregion of at least 25 base pairs, wherein said first nucleic strand is25-34 nucleotides in length and said second nucleic acid strand of saiddsNA is 26-50 nucleotides in length and comprises 1-5 single-strandednucleotides at its 3′ terminus and wherein: (a) said second nucleic acidstrand is complementary to SEQ ID NO:1128 along at least 20 contiguousnucleotides of said second nucleic acid strand and said double strandednucleic acid reduces HIF-1α target mRNA expression when said doublestranded nucleic acid is introduced into a mammalian cell; or (b) the 3′terminus of said first nucleic acid strand and the 5′ terminus of saidsecond nucleic acid strand form a blunt end, and said second nucleicacid strand is complementary to SEQ ID NO: 1128 along at least 20contiguous nucleotides of said second nucleic acid strand length andsaid double stranded nucleic acid reduces HIF-1α target mRNA expressionwhen said double stranded nucleic acid is introduced into a mammaliancell.
 24. The dsNA of claim 2, wherein the first nucleic acid strandcomprises SEQ ID NO: 750 and the second nucleic acid strand comprisingSEQ ID NO:
 372. 25. The dsNA of claim 1, wherein said second nucleicacid strand of said dsNA is complementary to SEQ ID NO: 1128 along atleast 20 contiguous nucleotides of said second nucleic acid strandlength.